Abstract 16898: Clinical Implementation of Pharmacogenomics Testing to Guide P2Y12 Inhibitor Use in Older Adults With Acute Coronary Syndrome: Insights From a Prospective Pilot Study

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sagune Sakya ◽  
CHRISTOPHER J Regan ◽  
Lionel Picot-Vierra ◽  
Ralph J Riello ◽  
Lydia Tran ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Pilot Study ◽  
Health System ◽  
Acceptance Rate ◽  
Clinical Implementation ◽  
Implementation Barriers ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome

Introduction: CYP2C19 testing is a known pharmacogenomics application to identify patients who can activate clopidogrel. Evidence-based guidelines now support second generation P2Y12 inhibitors over clopidogrel for the management of acute coronary syndrome (ACS). However, continued broad use of clopidogrel within our health-system indicated the potential value of pharmacogenomic testing to guide P2Y12 inhibitor prescribing. This study aimed to evaluate the clinical application of pharmacogenomic testing within a cardiovascular population and identify optimizations to the implementation process. Methods: This was a prospective, descriptive cohort pilot study at a large academic health-system. A high-impact pilot population included patients 65 years and older admitted for ACS who underwent percutaneous coronary intervention (PCI). Pharmacists identified eligible patients and made genomic-guided P2Y12 inhibitor recommendations for each patient. Surrogate markers of clinical impact included clopidogrel prescribing rates and quantification of active medication-gene interactions. Process indicators included acceptance rate of recommendations. Results: A total of 151 patients were included. At the time of result return, 46% of patients were on clopidogrel. Of these patients, 27% were identified as poor or intermediate metabolizers and were indicated for a change in therapy. The acceptance rate of genomic-guided recommendations was 42%. Identified barriers to uptake included result turnaround time limiting application of findings and unclear responsibility of follow-up. Conclusions: Results from this real-world study support implementation of CYP2C19 testing to guide P2Y12 inhibitor use. Identifying candidates for clopidogrel use through testing has potential clinical and cost benefits, but further studies are needed. Process optimizations are required to address implementation barriers and increase follow-up on actionable results.

Frequency and Reasons of Dual Antiplatelet Therapy Discontinuation and Switching of P2Y12 Inhibitors in Patients with Acute Coronary Syndrome Treated with Stent Implantation

Cardiology ◽  
2019 ◽  
Vol 142 (4) ◽  
pp. 203-207
Author(s):  
Georgina Fuertes Ferre ◽  
Isabel Caballero Jambrina ◽  
Alejandra Ruiz Aranjuelo ◽  
Javier Jimeno Sánchez ◽  
Jose Gabriel Galache Osuna ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Antiplatelet Therapy ◽  
Stent Implantation ◽  
Dual Antiplatelet Therapy ◽  
Antiplatelet Agent ◽  
Invasive Procedure ◽  
Medical Decisions ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome

Background: Incidence and reasons of dual antiplatelet therapy (DAPT) discontinuation and switching between P2Y12 inhibitors in acute coronary syndrome (ACS) patients treated with a stent have been poorly studied. Methods and Results: In a prospective single-center study, 283 consecutive patients presenting with ACS were treated with stent implantation between July 2015 and January 2016. Follow-up was achieved at 12 months in 273 patients using the electronic patient file and telephone interview. Switching from clopidogrel to a new antiplatelet agent (ticagrelor or prasugrel) or vice versa occurred in 60 (21.2%) patients. The most frequent reasons for switching were medical decisions not associated with bleeding events and concomitant use of chronic oral anticoagulation. Among the patients with a 1-year follow-up, 42 (15.4%) prematurely discontinued DAPT; 25 of them did so due to the need for an invasive procedure. DAPT premature discontinuation was not significantly associated with an increased 1-year risk of cardiovascular death or serious cardiac ischemic events (HR 2.08 [CI 95%: 0.88–4.94, p = 0.099]). Conclusions: DAPT discontinuation and switching between P2Y12 inhibitors are not uncommon in patients with ACS treated with a stent. The most frequent reasons were the need for an invasive procedure and medical decisions.

255Impact of the type of acute coronary syndrome on the pharmocodynamic response to P2Y12 inhibitors in the acute and maintenance phase of therapy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Lugo Gavidia ◽  
D Vivas ◽  
J M De La Hera ◽  
A Tello-Montoliu ◽  
A L Marcano ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Maintenance Phase ◽  
Platelet Inhibition ◽  
Clinical Indication ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
P2y12 Antagonists ◽  
St Elevation ◽  
The Impact

Abstract Background The presence of an acute coronary syndrome (ACS) is per se a predictor of reduced responsiveness to clopidogrel; in particular, patients with ST-elevation myocardial infarction (STEMI) have impaired clopidogrel-induced platelet inhibition than those with other forms of ACS. However, the impact of the type of ACS on the pharmocodynamic efficacy of more potent P2Y12 antagonists such as prasugrel or ticagrelor has not been fully elucidated to date. Purpose To assess the impact of the type of ACS on platelet inhibition mediated by P2Y12 receptor antagonists in the acute and the maintenance phase of therapy in a contemporary cohort of ACS patients undergoing percutaneous coronary intervention (PCI). Methods Substudy of a prospective, national, multicentre, pharmacodynamic registry conducted in a population of ACS patients undergoing PCI and treated with dual antiplatelet therapy including aspirin and a P2Y12 inhibitor as per clinical indication. Patients were classified according to the ACS diagnosis into groups: a) STEMI, b) non-ST-elevation ACS (NSTEACS), c) unstable angina (UA), and d) other (excluded from the present analysis). Platelet function tests (PFT) were performed at day 1 and day 30 (±5) after PCI and included: 1) VerifyNow P2Y12 assay, expressed as P2Y12 reaction units (PRUs); 2) Vasodilator-stimulated phosphoprotein (VASP) assay; and 3) Multiple electrode aggregometry (MEA). Results A total of 965 patients (372 with STEMI, 395 with NSTEACS and 198 with UA) were included in the present substudy. At day 1, the proportions of patients with each type of ACS according to the P2Y12 inhibitor received were: 1) clopidogrel (n=317): STEMI 35.0%, NSTEACS 34.4% and UA 30.6%; 2) prasugrel (n=192): STEMI 70.3%, NSTEACS 17.7% and UA 12.0%; 3) ticagrelor (n=456): STEMI 27.6%, NSTEACS 55.3% and UA 17.1%. A statistically significant reduced platelet inhibition, measured with the VerifyNow system, was observed in STEMI patients compared with the other forms of ACS in patients receiving clopidogrel (STEMI: 217.3±8.1, NSTEACS: 157.1±7.9 and UA: 164.9±8.6 PRUs; p for STEMI vs. NSTEACS <0.001 and p for STEMI vs. UA <0.001) and ticagrelor (STEMI: 57.7±3.8, NSTEACS: 45.2.1±2.6 and UA: 40.6±4.9 PRUs; p for STEMI vs. NSTEACS 0.008 and p for STEMI vs. UA 0.007), while a numerical trend towards greater platelet reactivity in STEMI compared to UA was observed in subjects receiving prasugrel (Figure). Remarkably, at day 30, no significant differences on platelet inhibition were observed according to the ACS type with any of the P2Y12 inhibitors. Similar results were observed with MEA and VASP assays. PD response according to the ACS type Conclusions Patients presenting with STEMI have impaired platelet inhibition mediated by P2Y12 antagonists compared to other types of ACS during the acute phase of therapy, whereas no difference is observed during the maintenance phase of treatment. Acknowledgement/Funding Funded by Instituto de Salud Carlos III through the project PI13/01012 (co-funded by European Regional Development Fund. ERDF, a way to build Europe)

P6412The AKR1D1*36 (rs1872930) allelic variant is independently associated with adverse cardiac events during Clopidogrel treatment

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
P Ugurov ◽  
A Kapedanovska-Nestorovska ◽  
R A Rosalia ◽  
A Dimovski ◽  
Z K Mitrev
Keyword(s):  
Risk Factors ◽  
Acute Coronary Syndrome ◽  
Antiplatelet Therapy ◽  
Allelic Variant ◽  
Time To Event ◽  
P2y12 Inhibitor ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
Cyp2c19 Polymorphisms

Abstract Background The treatment of acute coronary syndrome (ACS) includes dual antiplatelet therapy (DAPT) comprising of aspirin and a P2Y12 inhibitor; clopidogrel is usually the P2Y12 inhibitor of choice in patients with ACS. However, its efficacy has been questioned because of the relatively high incidence of Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) among ACS patients despite adherence to clopidogrel-DAPT. Several risk factors for MACCE following intervention in ACS patients have been described, among others, mutations in the CYP2C19 gene, a member of the cytochrome P450 (CYP450) network. The CYP2C19 enzyme is involved in the metabolism of clopidogrel Interindividual response variability to clopidogrel-DAPT and the increased risk for MACCE have been strongly linked to the CYP2C19*2 and CYP2C19*3 loss-of-function (LOF) allelic variants. Nonetheless, the known CYP2C19 polymorphisms fail to account for all adverse events related to clopidogrel insensitivity. Recent studies point to a putative role of the AKR1D1 gene as a trans-genetic regulator of the CYP450 network. The AKR1D1*36 (rs1872930) minor allelic variant was shown to augment hepatic CYP450 mRNA expression, consequently, increasing the CYP2C19 enzyme activity. To this end, we hypothesise that the AKR1D1*36 polymorphism contributes to the observed incidence of MACCE during clopidogrel antiplatelet therapy. Purpose To determine the association between the AKR1D1*36 (rs1872930) allele and MACCE in Acute Coronary Syndrome (ACS) patients on clopidogrel-DAPT Methods We evaluated 198 consecutive ACS patients indicated for coronary angiography from October to November 2010. We performed a 5-year retrospective medical record review and screened for AKR1D1 and CYP2C19 polymorphisms; 118 patients had a complete medical history and were included in the study. The study participants were prospectively followed for five years or until the first incidence of MACCE. The Median follow up time was 38.5 months (IQR 24–48 months) Results The median age of the cohort was 62.5 years (IQR 57–66), and 55% were females. Follow-up was complete, there were no mortality cases. ACS patients carrying the AKR1D1*36 had a significantly shorter event-free-survival compared to wildtype patients, Hazard Ratio = 2.193 [CI95% 1.091 to 4.406], p=0.0155 (Figure 1). Median time-to-event was 36 months. Evaluation of additional candidate risk predictors in a Cox Proportional Hazards Model confirmed the AKR1D1*36 allele as an independent risk factor (HR = 2.36; 95% CI, 1.34 to 4.18) and identified 3 additional risk factors for MACCE; previous percutaneous interventions (PCI), HR = 2.78; (95% CI, 1.34 to 5.78), a history of Myocardial Infarction, HR = 2.62; (95% CI, 1.48 to 4.64), at baseline and presence of the CYPC19*2 allele (HR = 2.33; 95% CI, 1.33 to 4.06). Figure 1. Time-to-Event curve of MACCE Conclusions The AKR1D1*36 (rs1872930) minor variant allele is independently associated with a higher risk for MACCE. Acknowledgement/Funding None

scholarly journals Reversible P2Y12 inhibitor versus irreversible P2Y12 inhibitor in ACS patients undergoing PCI (the acute coronary syndrome israeli survey (ACSIS)

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
R Eliaz ◽  
B Mengesha ◽  
T Ovdat ◽  
Z Iakobishvili ◽  
D Hasdai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Coronary Syndrome ◽  
Real Life ◽  
Coronary Intervention ◽  
Complication Rates ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Direct Head ◽  
St Elevation

Abstract Introduction Based on data from randomized controlled trials, both American and European guidelines recommend treating acute coronary syndrome (ACS) patients with second generation P2Y12 inhibitors.1,2 Direct head-to-head comparison of these agents was scarce until the recent publication of the ISAR-REACT-5 study which demonstrated the superiority of the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) over the reversible P2Y12 inhibitor in terms of 1-year composite of death, myocardial infarction (MI), and stroke.3,4,5 Given the unexpected outcomes of this trial, we sought to perform a comparison of ticagrelor and prasugrel in real-life ACS patients. Purpose To compare the outcomes of ACS (acute coronary syndrome) patients undergoing in-hospital PCI (percutaneous coronary intervention) treated with the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) versus the reversible P2Y12 inhibitor. Methods ACSIS (Acute Coronary Syndrome in Israel) is a national ACS snapshot survey conducted in all 25 cardiology departments in Israel since 2000 over a two-month period, every two to three years. Both the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) and the reversible P2Y12 inhibitor were commercially introduced in Israel in 2010. We therefore considered patients enrolled in ACSIS surveys 2010–2018 for the present analysis. Results Among 7,233 patients enrolled to the ACSIS (Acute Coronary Syndrome in Israel) registry between 2010 and 2018, we identified 1133 eligible patients treated with the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) and 825 with the reversible P2Y12 inhibitor. In hospital complication rates, including rates of stent thrombosis, were roughly similar between groups. Compared to the reversible P2Y12 inhibitor, the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) was associated with lower 1-year death in ST-elevation myocardial infarction (STEMI) patient compared to non-ST-elevation ACS (NSTE-ACS) patients (p for interaction 0.03). In propensity score matched STEMI patients (502 receiving the Irreversible thienopyridine type P2Y12 inhibitor (prodrug), 251 the reversible P2Y12 inhibitor) 30-day re-hospitalization rate (p&lt;0.05), 30-day MACE (the composite of death, MI, stroke, urgent revascularization; p=0.006), and 1-year mortality rates (p=0.08) were higher in the the reversible P2Y12 inhibitor group compared to the the Irreversible thienopyridine type P2Y12 inhibitor (prodrug) group; In NSTE-ACS patients, outcomes were not impacted by drug choice. Conclusion The Irreversible thienopyridine type P2Y12 inhibitor (prodrug) was more effective than the reversible P2Y12 inhibitor in STEMI patients, but not in NSTE-ACS patients. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): the Israeli working group on acute cardiac care of the Israel heart society

scholarly journals Effect of aspirin treatment duration on clinical outcomes in acute coronary syndrome patients with early aspirin discontinuation and received P2Y12 inhibitor monotherapy

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251109
Author(s):  
Ming-Yun Ho ◽  
Po-Wei Chen ◽  
Wen-Han Feng ◽  
Chun-Hung Su ◽  
Sheng-Wei Huang ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Clinical Outcomes ◽  
Treatment Duration ◽  
Composite Endpoint ◽  
Coronary Intervention ◽  
P2y12 Inhibitor ◽  
Safety Outcome ◽  
Coronary Syndrome ◽  
Percutaneous Coronary

Recent clinical trials showed that short aspirin duration (1 or 3 months) in dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy reduced the risk of bleeding and did not increase the ischemic risk compared to 12-month DAPT in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). However, it is unclear about the optimal duration of aspirin in P2Y12 inhibitor monotherapy. The purpose of this study was to evaluate the influence of aspirin treatment duration on clinical outcomes in a cohort of ACS patients with early aspirin interruption and received P2Y12 inhibitor monotherapy. From January 1, 2014 to December 31, 2018, we included 498 ACS patients (age 70.18 ± 12.84 years, 71.3% men) with aspirin stopped for various reasons before 6 months after PCI and received P2Y12 inhibitor monotherapy. The clinical outcomes between those with aspirin treatment ≤ 1 month and > 1 month were compared in 12-month follow up after PCI. Inverse probability of treatment weighting was used to balance the covariates between groups. The mean duration of aspirin treatment was 7.52 ± 8.10 days vs. 98.05 ± 56.70 days in the 2 groups (p<0.001). The primary composite endpoint of all-cause mortality, recurrent ACS or unplanned revascularization and stroke occurred in 12.6% and 14.4% in the 2 groups (adjusted HR 1.19, 95% CI 0.85–1.68). The safety outcome of BARC 3 or 5 bleeding was also similar (adjusted HR 0.69, 95% CI 0.34–1.40) between the 2 groups. In conclusion, patients with ≤ 1 month aspirin treatment had similar clinical outcomes to those with treatment > 1 month. Our results indicated that ≤ 1-month aspirin may be enough in P2Y12 inhibitor monotherapy strategy for ACS patients undergoing PCI.

Prasugrel in the treatment of acute coronary syndrome

2020 ◽  
Author(s):  
Michael Spartalis ◽  
Eleni Tzatzaki ◽  
Eleftherios Spartalis ◽  
Stavroula A Paschou ◽  
Antonios Athanasiou ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Rapid Onset ◽  
Cardiovascular Death ◽  
Major Adverse Cardiovascular Events ◽  
Onset Of Action ◽  
Action Current ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Increased Risk

Dual antiplatelet therapy is the mainstay therapy in patients with acute coronary syndrome. The combination of aspirin and a P2Y12 inhibitor in patients who receive a coronary stent reduces the rate of stent thrombosis and the rates of major adverse cardiovascular events. The newer P2Y12 inhibitors (prasugrel and ticagrelor) have better efficacy than clopidogrel. Prasugrel provides greater inhibition of platelet aggregation and has a rapid onset of action. Current acute coronary syndrome guidelines recommend the use of both newer P2Y12 inhibitors. However, emerging data have shown that prasugrel is more efficient than ticagrelor in reducing the incidence of nonfatal myocardial infarction, stroke or cardiovascular death, without increased risk of major bleeding.

Anticoagulation during and after acute coronary syndrome

2014 ◽  
Vol 34 (01) ◽  
pp. 72-77 ◽  
Author(s):  
C. Bode ◽  
A. Zirlik ◽  
I. Ahrens
Keyword(s):  
Acute Coronary Syndrome ◽  
Factor Xa ◽  
Thrombin Inhibitor ◽  
Third Generation ◽  
The Novel ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Novel Approach ◽  
Factor Xa Inhibition

SummaryCurrent antithrombotic therapy in patients with acute coronary syndrome (ACS) comprises antiplatelet and anticoagulant therapy. Dual antiplatelet therapy composed of aspirin plus a third generation P2Y12 inhibitor (prasugrel or ticagrelor) represents the gold standard, while aspirin plus second generation P2Y12 inhibitor (clopidogrel) may be used as an alternative in the presence of contraindications for third generation P2Y12 inhibitors and/or a high risk of bleeding. Unfractionated heparin (UFH) has been the unchallenged mainstay in anticoagulation for ACS for many decades and is still widely used in patients with ACS treated interventionally. Novel alternative parenteral anticoagulant strategies include the low molecular weight heparin enoxaparin and the synthetic pentas-accharide fondaparinux. Both of these agents share advantages over UFH particularly in medically treated patients with ACS not scheduled for PCI. The direct parenteral factor IIa (thrombin) inhibitor bivalirudin, when used as sole anticoagulant in patients with ACS undergoing PCI, is as effective as the regimen of UFH plus GPIIb/IIIa inhibitor in NSTEMI and superior to the latter regimen in patients with STEMI. The novel approach of a long-term low dose factor Xa inhibition with rivaroxaban in the post ACS phase even further reduced cardiovascular mortality in a clinical trial but has yet to be established in daily clinical practice in the setting of third generation P2Y12 inhibitors. This review discusses currently clinically established anticoagulants for the treatment of ACS alongside with novel approaches such as rivaroxaban.

scholarly journals P2Y12 Inhibitor Utilization for Acute Coronary Syndrome in the Elderly: A Provincial Analysis From 2008 to 2018

2020 ◽  
Author(s):  
Saurabh Gupta ◽  
Emilie P Belley-Cote ◽  
Adam Eqbal ◽  
Charlotte McEwen ◽  
Ameen Basha ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Antiplatelet Therapy ◽  
Drug Coverage ◽  
Publicly Funded ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Medication Plan ◽  
Cabg Patients ◽  
Health Canada

Abstract Background Guidelines recommend acetylsalicylic acid (ASA) and ticagrelor following acute coronary syndrome (ACS), but appropriate prescription practices lag. We analyzed the impact of government medication approval, national guideline updates, and publicly funded drug coverage plans on P2Y12 inhibitor utilization.Methods Accessing provincial databases, we obtained data for elderly ACS patients in Ontario, Canada between 2008 and 2018. Using an interrupted-time series, we evaluated types of P2Y12 inhibitors prescribed at discharge, and changes to their utilization following ticagrelor’s national approval by Health Canada, national antiplatelet therapy guidelines (by the Canadian Cardiovascular Society (CCS)), and ticagrelor's coverage by a publicly funded medication plan.Results We included 114,142 patients (49.4%-PCI and 7.7%-CABG). Proportion of PCI patients utilizing P2Y12 inhibitors increased from 73.4% to 86.9% (p<0.001) and 11.4% to 46.5% (p<0.001) for CABG patients. Among PCI patients, clopidogrel utilization declined monthly after 2010 national guidelines were published (0.7%; p<0.0001) and within the first month after ticagrelor’s national approval by Health Canada (5.3%; p=0.03). Among PCI patients, ticagrelor utilization increased within the first month (24.5%; p<0.0001) and continued increasing monthly (0.4%; p<0.0001) after its coverage by a publicly funded medication plan. Among CABG patients, ticagrelor’s coverage was associated with a monthly increase in its utilization (0.2%; p<0.0001). Among PCI patients, clopidogrel utilization declined within the first month (6.1%; p=0.003) and ticagrelor utilization increased monthly (0.3%; p=0.05) after 2012 CCS guidelines.Conclusion National guideline updates and drug coverage by a publicly funded medication plan significantly improved P2Y12 inhibitor utilization. Barriers to appropriate antiplatelet therapy in the surgical population must be explored.

scholarly journals EARLY PRESCRIPTION OF PLATELET P2Y12 RECEPTOR INHIBITORS TO PATIENTS WITH ACUTE CORONARY SYNDROME: A BENEFIT OR A HARM?

2018 ◽  
pp. 76-86
Author(s):  
Roman M. Shakhnovich
Keyword(s):  
Acute Coronary Syndrome ◽  
Coronary Angiography ◽  
Secondary Prevention ◽  
Randomized Trials ◽  
P2y12 Receptor ◽  
Coronary Anatomy ◽  
P2y12 Inhibitor ◽  
P2y12 Inhibitors ◽  
Coronary Syndrome ◽  
Main Component

Double antiplatelet therapy, which includes aspirin and platelet P2Y12 receptor inhibitors (hereinafter P2Y12 inhibitor) is the main component of treatment and secondary prevention after ACS. In recent years, the issue of determining whether it is expedient for P2Y12 inhibitors to be early prescribed to patients with ACS – prior to coronary angiography, when coronary anatomy is unknown – has been widely debated. The review provides comprehensive up-to-date information on this topic based on data from randomized trials, registers, and official clinical guidelines.

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