Bivalirudin in acute coronary syndromes and percutaneous coronaryVishwanath Hesarur
Anti-thrombotic therapy remains a cornerstone in per-cutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) management.
The search for newer anti-thrombotic drugs is ongoing with the goal to achieve an agent which leads to less bleeding complications without a reduction or indeed improvement in clinical efficacy, resulting in net clinical benefit.
This is because major bleeding remains a significant risk factor for mortality following PCI with higher 30 days and one year mortality reported in numerous studies .
Bleeding is associated with a five-fold increase in mor-tality and higher risk of myocardial infarction, stroke and stent thrombosis in ACS .
A ruptured or eroded coronary atherosclerotic plaque is the principal underlying cause of an acute coronary syndrome. The greatest ‘at risk’ period is during this early phase of plaque instability and healing, with recurrent event rates peaking in the first month. By 3 months, the plaque has usually
stabilised, healed and subsequent event rates return
to the background rates seen in patients with stable
coronary heart disease.1–3 Indeed, beyond 3 months,
recurrent events commonly occur on plaques at
other sites within the coronary circulation.3 From
first principles, the first 3 months is the most critical
time for interventions to reduce recurrent cardiovascular
events after an acute coronary syndrome
(ACS). This is consistent with event rates seen in
all clinical trials of patients with acute coronary syndrome: an initial time-varying high event rate that reverts to a consistent linear lower event rate from 3 months onwards
Bivalirudin in acute coronary syndromes and percutaneous coronaryVishwanath Hesarur
Anti-thrombotic therapy remains a cornerstone in per-cutaneous coronary intervention (PCI) and acute coronary syndrome (ACS) management.
The search for newer anti-thrombotic drugs is ongoing with the goal to achieve an agent which leads to less bleeding complications without a reduction or indeed improvement in clinical efficacy, resulting in net clinical benefit.
This is because major bleeding remains a significant risk factor for mortality following PCI with higher 30 days and one year mortality reported in numerous studies .
Bleeding is associated with a five-fold increase in mor-tality and higher risk of myocardial infarction, stroke and stent thrombosis in ACS .
A ruptured or eroded coronary atherosclerotic plaque is the principal underlying cause of an acute coronary syndrome. The greatest ‘at risk’ period is during this early phase of plaque instability and healing, with recurrent event rates peaking in the first month. By 3 months, the plaque has usually
stabilised, healed and subsequent event rates return
to the background rates seen in patients with stable
coronary heart disease.1–3 Indeed, beyond 3 months,
recurrent events commonly occur on plaques at
other sites within the coronary circulation.3 From
first principles, the first 3 months is the most critical
time for interventions to reduce recurrent cardiovascular
events after an acute coronary syndrome
(ACS). This is consistent with event rates seen in
all clinical trials of patients with acute coronary syndrome: an initial time-varying high event rate that reverts to a consistent linear lower event rate from 3 months onwards
Ticagrelor in acute myocardial infarctionVasif Mayan
Potential benefits of dual antiplatelet therapy beyond 1 year after an MI has not been studied
Patients with MI are at increased risk of RECURRENT ISCHAEMIC EVENTS
Intensive secondary prevention is theoretically beneficial
Finding an ideal drug with best risk-benefit ratio is a challenge
TICAGRELOR
--- Direct acting
Not a pro-drug; does not require metabolic activation
Rapid onset of inhibitory effect on the P2Y12 receptor
Greater inhibition of platelet aggregation than clopidogrel
--- Reversibly bound
Degree of inhibition reflects plasma concentration
Faster offset of effect than clopidogrel
Functional recovery of circulating platelets within ~48 hours
PLATO trial
PEGASUS TIMI trial
Dual antiplatelet therapy has long been the standard of care in preventing coronary and cerebrovascular thrombotic events in patients
with chronic coronary syndrome and acute coronary syndrome undergoing percutaneous coronary intervention, but choosing the optimal
treatment duration and composition has become a major challenge. Numerous studies have shown that certain patients benefit from ei ther shortened or extended treatment duration. Furthermore, trials evaluating novel antithrombotic strategies, such as P2Y12 inhibitor
monotherapy, low-dose factor Xa inhibitors on top of antiplatelet therapy, and platelet function- or genotype-guided (de-)escalation of
treatment, have shown promising results. Current guidelines recommend risk stratification for tailoring treatment duration and composition. Although several risk stratification methods evaluating ischaemic and bleeding risk are available to clinicians, such as the use of risk
scores, platelet function testing , and genotyping, risk stratification has not been broadly adopted in clinical practice. Multiple risk scores
have been developed to determine the optimal treatment duration, but external validation studies have yielded conflicting results in terms
of calibration and discrimination and there is limited evidence that their adoption improves clinical outcomes. Likewise, platelet function
testing and genotyping can provide useful prognostic insights, but trials evaluating treatment strategies guided by these stratification methods have produced mixed results. This review critically appraises the currently available antithrombotic strategies and provides a viewpoint
on the use of different risk stratification methods alongside clinical judgement in current clinical practice.
Platelet Aggregation Inhibitor Ticagrelor(274693-27-5) for saleticagrelor
Ticagrelor(274693-27-5) is a platelet aggregation inhibitor, It keeps the platelets in your blood from coagulating (clotting) to prevent unwanted blood clots. Visit: http://www.aasraw.com/products/ticagrelor-powder/
Ticagrelor in acute myocardial infarctionVasif Mayan
Potential benefits of dual antiplatelet therapy beyond 1 year after an MI has not been studied
Patients with MI are at increased risk of RECURRENT ISCHAEMIC EVENTS
Intensive secondary prevention is theoretically beneficial
Finding an ideal drug with best risk-benefit ratio is a challenge
TICAGRELOR
--- Direct acting
Not a pro-drug; does not require metabolic activation
Rapid onset of inhibitory effect on the P2Y12 receptor
Greater inhibition of platelet aggregation than clopidogrel
--- Reversibly bound
Degree of inhibition reflects plasma concentration
Faster offset of effect than clopidogrel
Functional recovery of circulating platelets within ~48 hours
PLATO trial
PEGASUS TIMI trial
Dual antiplatelet therapy has long been the standard of care in preventing coronary and cerebrovascular thrombotic events in patients
with chronic coronary syndrome and acute coronary syndrome undergoing percutaneous coronary intervention, but choosing the optimal
treatment duration and composition has become a major challenge. Numerous studies have shown that certain patients benefit from ei ther shortened or extended treatment duration. Furthermore, trials evaluating novel antithrombotic strategies, such as P2Y12 inhibitor
monotherapy, low-dose factor Xa inhibitors on top of antiplatelet therapy, and platelet function- or genotype-guided (de-)escalation of
treatment, have shown promising results. Current guidelines recommend risk stratification for tailoring treatment duration and composition. Although several risk stratification methods evaluating ischaemic and bleeding risk are available to clinicians, such as the use of risk
scores, platelet function testing , and genotyping, risk stratification has not been broadly adopted in clinical practice. Multiple risk scores
have been developed to determine the optimal treatment duration, but external validation studies have yielded conflicting results in terms
of calibration and discrimination and there is limited evidence that their adoption improves clinical outcomes. Likewise, platelet function
testing and genotyping can provide useful prognostic insights, but trials evaluating treatment strategies guided by these stratification methods have produced mixed results. This review critically appraises the currently available antithrombotic strategies and provides a viewpoint
on the use of different risk stratification methods alongside clinical judgement in current clinical practice.
Platelet Aggregation Inhibitor Ticagrelor(274693-27-5) for saleticagrelor
Ticagrelor(274693-27-5) is a platelet aggregation inhibitor, It keeps the platelets in your blood from coagulating (clotting) to prevent unwanted blood clots. Visit: http://www.aasraw.com/products/ticagrelor-powder/
Bleeding complications in secondary stroke prevention by antiplatelet therapy...Duwan Arismendy
Abstract
Abstract. Boysen G (University of Copenhagen, Copenhagen, Denmark). Bleeding complications in secondary stroke prevention by antiplatelet therapy: a benefit–risk analysis (Review). J Intern Med 1999; 246: 239–245.
This review analyses the benefit–risk ratio of antiplatelet drugs in secondary stroke prevention and is based on the published data from eight large stroke prevention trials. In patients with prior transient ischaemic attack (TIA) or stroke, aspirin prevented one to two vascular events (stroke, AMI, or vascular death) per 100 treatment-years with an excess risk of fatal and severe bleeds of 0.4–0.6 per 100 treatment-years. The gastrointestinal bleeding risk was significantly lower with ticlopidine and clopidogrel, which were both somewhat more effective than aspirin in the prevention of vascular events. The combination of dipyridamole and aspirin prevented 2.82 strokes at the expense of an excess risk of 0.61 (95% CI = 0.27–0.95) fatal or severe bleeds per 100 treatment-years.
In the acute phase of stroke, the aspirin-associated risk of haemorrhagic complications was much increased compared with that in the stable phase after stroke, with 0.48 (95% CI = 0.13–0.83) fatal or severe bleeds per 100 treated patients for the first 4 weeks after stroke in the Chinese Acute Stroke Trial and 0.41 (95% CI = 0.05–0.77) in the International Stroke Trial. Still, there was a net benefit with the prevention of about one death or non-fatal ischaemic stroke per 100 treated patients.
A primary Percutaneous Coronary Intervention (PCI) Primary PCI continues to be the optimal reperfusion therapy in
patients with ST elevation myocardial infarction however, in areas where PCI centers are not readily available, a pharmaco-invasive strategy has been proposed. This study investigated the safety, efficacy and cost effective analysis of a pharmaco-invasive strategy compared with primary (PCI) strategy for ST-Segment Elevation Myocardial Infarction (STEMI) in Gaza.
Methods: We ran domized 145 patients presenting within 2 hours of symptom onset of acute ST elevation myocardial infarction to primary PCI or for pharmaco-invasive PCI 2-24 hours after streptokinase, except in the event of failed reperfusion, in which case, emergency angiography was recommended. The primary endpoint a composite of death, shock and congestive heart failure at 30 days. Secondary end points: total bleeding and failed streptokinase required emergent PCI. Tertiary end points: cost effective analysis.
Impact of statins and beta-blocker therapy on mortality after coronary artery...Paul Schoenhagen
Background: We conducted a retrospective cohort study of patients after first-time isolated coronary artery bypass graft surgery (CABG) and assessed the impact of a discharge regimen including beta-blockers and statin therapy and their relationship to long-term all cause mortality and major adverse cardiovascular events (MACE).
Methods: We identified patients age >18 years, undergoing first time isolated CABG from 1993 to 2005. Patients were identified using the Cardiovascular Information Registry (CVIR). We collected follow-up information at 30, 60, 90 days and yearly follow-up. The registry is approved for use in research by the institutional review broad.
Results: We identified 5,205 patients who underwent single isolated CABG between January 1993 and December 2005. The mean age was 64.5±9.7 years and over 70% were male. There was a significant difference in the low density lipoproteins (LDL) concentration between those with or without statin medications (134±41.9 mg/dL) (no statin) vs. 126±44.8 mg/dL (with statin), P=0.001. A discharge regimen with statin therapy was associated with and overall reduction in 30 day, 1 year and long-term mortality. In addition, overall the triple ischemic endpoint of death, myocardial infarction (MI) and stroke was also significantly lower in the statin vs. no-statin group. In addition, statin and beta-blockers exerted synergistic effect on overall mortality outcomes short-term and in the long-term. We note that the predictors of overall death include no therapy with statin therapy and age [hazard ratios (HR) 1.1, 95% CI: 1.04-1.078, P<0.001] and presence of renal failure (HR 2.0, P=0.005). The estimated 11-year Kaplan Meier curves for mortality between the two groups starts to diverge immediately post discharge after single isolated CABG and continue to diverge through out the follow-up period.
Conclusions: A post-discharge regimen of statins independently reduces overall and 1 year mortality. These results confirm those of earlier studies within a contemporary surgical population and support the current clinical guidelines.
Impact of statins and beta-blocker therapy on mortality after coronary artery...Paul Schoenhagen
Abstract
Background: We conducted a retrospective cohort study of patients after first-time isolated coronary artery bypass graft surgery (CABG) and assessed the impact of a discharge regimen including beta-blockers and statin therapy and their relationship to long-term all cause mortality and major adverse cardiovascular events (MACE).
Methods: We identified patients age >18 years, undergoing first time isolated CABG from 1993 to 2005. Patients were identified using the Cardiovascular Information Registry (CVIR). We collected follow-up information at 30, 60, 90 days and yearly follow-up. The registry is approved for use in research by the institutional review broad.
Results: We identified 5,205 patients who underwent single isolated CABG between January 1993 and December 2005. The mean age was 64.5±9.7 years and over 70% were male. There was a significant difference in the low density lipoproteins (LDL) concentration between those with or without statin medications (134±41.9 mg/dL) (no statin) vs. 126±44.8 mg/dL (with statin), P=0.001. A discharge regimen with statin therapy was associated with and overall reduction in 30 day, 1 year and long-term mortality. In addition, overall the triple ischemic endpoint of death, myocardial infarction (MI) and stroke was also significantly lower in the statin vs. no-statin group. In addition, statin and beta-blockers exerted synergistic effect on overall mortality outcomes short-term and in the long-term. We note that the predictors of overall death include no therapy with statin therapy and age [hazard ratios (HR) 1.1, 95% CI: 1.04-1.078, P<0.001] and presence of renal failure (HR 2.0, P=0.005). The estimated 11-year Kaplan Meier curves for mortality between the two groups starts to diverge immediately post discharge after single isolated CABG and continue to diverge through out the follow-up period.
Conclusions: A post-discharge regimen of statins independently reduces overall and 1 year mortality. These results confirm those of earlier studies within a contemporary surgical population and support the current clinical guidelines.
Presentations by Tawfiq Choudhury and Rocco Hadland from the second webinar of the Mastering Cholesterol webinar series on Thursday 11 May 2023, focusing on Statins.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
Ethnobotany and Ethnopharmacology:
Ethnobotany in herbal drug evaluation,
Impact of Ethnobotany in traditional medicine,
New development in herbals,
Bio-prospecting tools for drug discovery,
Role of Ethnopharmacology in drug evaluation,
Reverse Pharmacology.
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
This slides describes the basic concepts of ICT, basics of Email, Emerging Technology and Digital Initiatives in Education. This presentations aligns with the UGC Paper I syllabus.
The Art Pastor's Guide to Sabbath | Steve ThomasonSteve Thomason
What is the purpose of the Sabbath Law in the Torah. It is interesting to compare how the context of the law shifts from Exodus to Deuteronomy. Who gets to rest, and why?
How to Create Map Views in the Odoo 17 ERPCeline George
The map views are useful for providing a geographical representation of data. They allow users to visualize and analyze the data in a more intuitive manner.
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
2. Contemporary Antiplatelet Strategies in the Treatment of STEMI using PPCI
INTERVENTIONAL C ARDIO LO G Y REVIEW 27
values for ADP-induced platelet aggregation 4 hours after drug
administration. The clinical benefit of a 600 mg loading dose in STEMI
patients undergoing PPCI was demonstrated in the Antiplatelet
therapy for reduction of myocardial damage during angioplasty
(ARMYDA)-6 MI,9
Clopidogrel and aspirin optimal dose usage to
reduce recurrent events – seventh organisation to assess strategies
in ischemic symptoms (CURRENT-OASIS) 710
and Harmonising
outcomes with revascularisation and stents in acute myocardial
infarction (HORIZONS-AMI)11
trials. In ARYMDA-6 MI, high dose loading
reduced infarct size with improved cardiac function, and 30-day
MACE rates. Similarly, in subgroup analyses of the CURRENT-OASIS
7 and HORIZONS-AMI trials, STEMI patients loaded with clopidogrel
600 mg, prior to PPCI, had a significant reduction in stent thrombosis
and myocardial infarction, without any increase in bleeding events.
Prasugrel
Prasugrel is a third-generation thienopyridine, sharing the same active
metabolite as clopidogrel (see Figure 2), and despite partial reliance on
CYP2C19, achieves faster and more potent platelet inhibition (a 60 mg
loading dose of prasugrel reaches maximal plasma concentration at 30
minutes in healthy volunteers).12
Prasugrel has a very low rate of non-
responders in comparison with clopidogrel.13
The clinical superiority of prasugrel over clopidogrel in ACS was
demonstrated in the TRial to assess Improvement in Therapeutic
Outcomes by optimising platelet inhibitioN – Thrombolysis in Myocardial
Infarction-38 (TRITON–TIMI 38) study.14
Prasugrel, administered
following angiography, reduced the composite primary endpoint
(cardiovascular death, non-fatal MI or stroke) in patients undergoing
PCI for STEMI or moderate-high risk ACS. In the pre-specified STEMI
subgroup (3,534 patients), the risk reduction was 21 % (prasugrel 10 %
versus clopidogrel 12.4 %) at 15 months, without a significant increase
in non-coronary artery bypass graft (CABG)-related bleeding.15
The risk
of stent thrombosis was also significantly lower.
Prasugrel is contraindicated in patients with prior stroke/transient
ischaemic attack (TIA), and is not recommended in patients aged ≥75
years or in patients with lower body weight (<60 kg), as there was no net
clinical benefit in these subsets. A reduced maintenance dose of 5 mg
could be considered in these patients.
Ticagrelor
A new chemical class called CycloPentylTriazoloPyrimidine is partly
formed by Ticagrelor, which, in contrast to thienopyridines, causes
reversible inhibition of the P2Y12 receptor and does not require
hepatic metabolism for its activity (see Figure 2).16
Similar to prasugrel,
ticagrelor provides more rapid, potent and consistent platelet inhibition
over clopidogrel.
In the PLATelet inhibition and patient Outcomes (PLATO) trial,17
ticagrelor
(compared with clopidogrel) reduced the composite primary endpoint
(cardiovascular death, non-fatal MI or stroke) and also reduced
cardiovascular mortality in STEMI and moderate–high risk ACS patients.
In the STEMI subgroup, this primary endpoint was reduced from 10.8 %
in the clopidogrel group to 9.4 % in the ticagrelor group (relative risk [RR]
reduction of 13 %). In addition, overall mortality was reduced from 6 %
to 4.9 % without a higher risk of major bleeding.
Dyspnoea is a frequently reported side effect of ticagrelor. In PLATO,
13.8 % of patients on ticagrelor reported dyspnoea compared with 7.8 %
treated with clopidogrel.17
However few patients (0.9 %) discontinued the
drug because of dyspnoea; importantly, there were no associated lung
abnormalities and the mortality benefit persisted in this group.18
Contrary
to the PLATO experience, a recent study of ticagrelor compliance in ACS
patients demonstrated that dyspnoea was the commonest reason for
drug discontinuation, occurring in 9.1 % of cases.19
The European Society of Cardiology (ESC) and American College
of Cardiology Foundation/American Heart Association (ACCF/AHA)
recommendations for antithrombotic strategies in patients with STEMI
undergoing primary PCI are summarised in Table 1. Prasugrel, ticagrelor
and clopidogrel (600 mg loading dose) are all class I, level B options in
both guidelines, but the ESC expresses a clear preference for the newer
antiplatelet agents, stating that clopidogrel should only be used when
prasugrel or ticagrelor are either not available or contraindicated.
Figure 1: Timeline of a STEMI Patient Requiring PPCI and
Pharmacotherapy Options
Figure 2: Molecular Targets of Drug Therapy on the
Activated Platelet
Aspirin (Morphine,
Oxygen Therapy)
CTB Time*
113 mins
DTB Time*
39 mins
Antiplatelet Therapy
pre-PPCI
Clopidogrel or Prasugrel
or Ticagrelor
Heparin or Bivalirudin +/- GP
IIb/IIIa Inhibitor
Aspirin + Clopidogrel or
Prasugrel or Ticagrelor
(Warfarin and (N)OACs)
Symptom Onset
First Medical
Contact
Diagnosis and
Decision for PPCI
Arrival at PPCI
Centre
Post PPCI
PPCI
}
*Median times based on British Cardiovascular Intervention Society Audit Returns 2013.
CTB = call to balloon; DTB = door to balloon; GPIIb/IIIa = glycoprotein IIb/IIIa; (N)OAC = non-
vitamin K antagonist oral anticoagulants; PPCI = primary percutaneous coronary intervention.
AA = arachidonic acid; COX-1 = cyclooxygenase-1; CYP450 = cytochrome P450;
P2Y12 = purinergic receptor P2Y; GPIIb/IIIa = glycoprotein IIb/IIIa; TXA2 = thromboxane A2.
Prasugrel
Ticagrelor
Clopidogrel
active
metabolite
CP450
P2Y12
P2Y12
CP450
CP450
GPIIb/IIIa Inhibitors
TXA2
COX-1
AA
Platelet Activation
Abxicimab
Eptifibatide
Tirofiban
Aspirin
Johnson_FINAL.indd 27 26/02/2015 22:12
3. Coronary Adjunctive Pharmacotherapy
INT ERVENT IONAL CARDIOLOGY REVIEW28
Glycoprotein IIb/IIIa Inhibitors
Glycoprotein IIb/IIIa inhibitors (GPIs) provide rapid, potent platelet
inhibition. Their use in PPCI has spanned the evolution of PCI and
pharmacological therapies; consequently, it is challenging to relate the
data to current practice with more potent oral antiplatelet therapies.
Initial data supported the combined role of stenting and abciximab
administration to minimise target vessel revascularisation,20
and pre-
angiographic commencement of therapy appeared advantageous.21
However, in the dual antiplatelet therapy (DAPT) era, early use of
abciximab resulted in an increased rate of bleeding.22
Subsequent
analysis has demonstrated a continued benefit in early administration
of GPIs in high-risk patients,23
particularly if presenting early or to a
non-interventional centre.24
Contemporary trials provide conflicting
results, the ONgoing Tirofiban in Myocardial infarction Evaluation 2
(ON-TIME 2) trial,25
utilising pre-hospital initiation of high bolus dose
tirofiban, in addition to aspirin, heparin and high-dose clopidogrel,
reduced MACE at 30 days with no significant increase in major
bleeding. However, the HORIZONS-AMI26
trial demonstrated superiority
of bivalirudin versus unfractionated heparin (UFH) and GPI in terms of
a composite of major bleeding and MACE. Consequently, current
guidelines1,4
suggest restricting GPI use for ‘bailout’ in the event of
angiographic evidence of massive thrombus, slow-/no-reflow or a
thrombotic complication.
Adjunctive Antithrombotic Pharmacotherapy
during PPCI
In addition to the array of oral antiplatelet therapy options in PPCI, there
is continued debate regarding the optimal combination of antithombotic
Table 1: Recommendations for Antithrombotic Treatment Strategies in Patients with STEMI Undergoing Primary PCI
Recommendations Class of Recommendation
ESC1 ACCF/AHA3
Antiplatelet Therapy
Aspirin
Recommended in all patients regardless of initial treatment strategy I I
In Europe: Loading dose 150–300mg oral (or 80–150mg i.v.), maintenance dose 75–100mg daily long term I
In America: Loading dose 162–325mg oral, maintenance 81–325mg daily long term (81 mg preferred with
Ticagrelor – Class IIa)
I
P2Y12 Inhibitor
Recommended in addition to aspirin and maintained over 12 months I I
Give at time of first medical contact (ESC); as early as possible or at time of PCI (AHA/ACCF) I I
Options:
Prasugrel (60 mg loading dose, 10 mg daily dose) if no contraindication (i.e. prior stroke/TIA) I I
Ticagrelor (180 mg loading dose, 90 mg twice daily dose) if no contraindication I I
Clopidogrel (600 mg loading dose, 75 mg daily dose). ESC: only when prasugrel or ticagrelor are not
available or contraindicated
I I
GPIIb/IIIa Inhibitor
Should be considered for bail-out or evidence of no re-flow or a thrombotic complication IIa IIa
Upstream use may be considered for high-risk patients undergoing transfer for primary PCI IIb IIb
Options are: abxicimab, eptifibatide (with double bolus) or tirofiban (with a high bolus dose)
Anticoagulant Therapy
Recommended in all patients in addition to antiplatelet therapy I I
Options:
Unfractionated heparin (70–100 U/kg i.v. bolus when no GPIIb/IIIa inhibitor is planned; 50–70 U/kg i.v.
bolus with GPIIb/IIIa inhibitor)
I I
Bivalirudin 0.75 mg/kg i.v. bolus followed by i.v. infusion of 1.75 mg/kg/h for up to 4 hours post procedure IIa I
Bivalirudin is preferred over UFH with GPIIb/IIIa receptor antagonist in patients at high risk of bleeding IIa
Enoxaparin i.v. 0.5 mg/kg with or without GPIIb/IIIa inhibitor IIa
Antiplatelet Therapy after PCI in Patients Requiring Oral Anticoagulation
In patients with a firm indication for oral anticoagulation (e.g. atrial fibrillation with CHA2
DS2
-VASc score ≥2,
venous thromboembolism, LV thrombus or mechanical valve prosthesis), oral anticoagulation is recommended
in addition to antiplatelet therapy
I
In patients with ACS and atrial fibrillation at low bleeding risk (HAS-BLED ≤2), initial triple therapy of (N)OAC and
ASA (75–100 mg/day) and clopidogrel 75 mg/day should be considered for a duration of 6 months irrespective of
stent type followed by (N)OAC and aspirin 75–100 mg/day or clopidogrel (75 mg/day) continued up to 12 months
IIa
In patients requiring oral anticoagulation at high bleeding risk (HAS BLED ≥3), triple therapy of (N)OAC and ASA
(75–100 mg/day) and clopidogrel 75 mg/day should be considered for a duration of 1 month irrespective of stent
type followed by (N)OAC and aspirin 75–100 mg/day or clopidogrel (75 mg/day) continued up to 12 months
IIa
The use of ticagrelor and prasugrel as part of initial triple therapy is not recommended III
ACCF/AHA = American College of Cardiology Foundation/American Heart Association; ACS = acute coronary syndrome; ASA = acetylsalicylic acid; CHA2DS2-VASc = Cardiac failure,
Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled] – Vascular disease, Age 65 – 74 and Sex category [Female]); ESC = European Society of Cardiology; GPIIb/IIIa = glycoprotein
IIb/IIIa; HAS-BLED = hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol; INR = international normalized ratio; LV = left
ventricular; (N)OAC = (non-vitamin K antagonist) oral anticoagulant; PCI = percutaneous coronary intervention; STEMI = ST elevation myocardial infarction; TIA = transient ischaemic attack;
UFH = unfractionated heparin.
Johnson_FINAL.indd 28 26/02/2015 22:12
4. Contemporary Antiplatelet Strategies in the Treatment of STEMI using PPCI
INTERVENTIONAL C ARDIO LO G Y REVIEW 29
therapy. UFH and bivalirudin are most commonly used and the European
guidelines for STEMI support their use with a Class I indication.27
The evidence supporting use of bivalirudin derived from HORIZONS-
AMI,26
which demonstrated that bivalirudin compared with UFH and
routine use of GPIs was associated with a reduction in mortality
and major bleeding at 30 days, with a survival benefit that extended
to 3 years. Further support for bivalirudin’s bleeding safety was
demonstrated in the open-label European Ambulance ACS Angiography
(EUROMAX) trial,28
comparing pre-hospital administration of bivalirudin
versus UFH or low-molecular-weight heparin (LMWH) with optional use
of GPI (58.5 % routine use). However, both trials were associated with
an increased rate of AST with the use of bivalirudin and the elevated
bleeding rate observed in the UFH arm of both studies has been
attributed to the high rates of GPI use.
The recently published How Effective are Antithrombotic Therapies in
primary percutaneous coronary intervention (HEAT-PPCI) trial29
was
designed to specifically address the criticisms levelled at previous
bivalirudin trials, specifically the efficacy of bivalirudin monotherapy
against UFH with GPI use restricted to true ‘bail-out’ (13 % and 15 %,
respectively). The study demonstrated a primary efficacy outcome (all-
cause mortality, cerebrovascular accident, re-infarction or unplanned
target lesion revascularisation) of 8.7 % in the bivalirudin group versus
5.7 % in the heparin group (RR 1.52, 95 % confidence interval [CI] 0.9–
2.13). This reduction in major adverse ischaemic events with heparin
was not associated with an increase in bleeding complications. Definite
or probable stent thrombosis occurred more often with bivalirudin (3.4
versus 0.9 %, RR 3.91, 95 % CI 1.61–9.52). In the light of these new data,
the most recent ESC guidelines on revascularisation have downgraded
their recommendation for the use of bivalirudin to Class IIa1
.
Acute Stent Thrombosis
The increased rate of AST observed with bivalirudin therapy has been
attributed to the relatively short half life of bivalirudin (t1/2
=25 minutes),30
resulting in a waning effect of the drug within 2 hours of withdrawal.
The risk of AST is further exacerbated by the observed delay in
platelet inhibition observed in STEMI patients treated with oral P2Y12
inhibitors. The Rapid Activity of Platelet Inhibitor Drugs (RAPID) Primary
PCI study31
evaluated 50 patients with STEMI undergoing PPCI with
bivalirudin monotherapy, randomised to prasugrel or ticagrelor at
standard loading doses. There was no significant difference in residual
platelet reactivity between both drugs but the study showed that
effective platelet inhibition within 2 hours of loading was only achieved
in half of patients. Four hours were required to achieve effective
platelet inhibition in the majority of patients.
Morphine Effect on Platelet Activity
The RAPID investigators assessed the effect of opiate use on platelet
reactivity. The use of morphine significantly affected the activity
of prasugrel and ticagrelor, independently predicting high residual
platelet reactivity 2 hours post-loading dose (odds ratio 5.29;
p=0.012).31
The effect has been confirmed in a randomised controlled
trial of 24 healthy subjects receiving 600 mg of clopidogrel with
placebo or 5 mg of intravenous morphine. Morphine was shown to
delay clopidogrel absorption, decrease plasma levels of the active
metabolite and delayed the maximal inhibition of platelet aggregation
by 2 hours.32
Furthermore, the opiate effect on platelet inhibition
does not appear restricted to patients experiencing opiate-related
nausea/vomiting.33
The negative interaction between morphine and oral antiplatelet
agents is also supported by the Administration of ticagrelor in the
cathlab or in the ambulance for new STEMI to open the coronary
artery (ATLANTIC) trial,34
which demonstrated that the primary end
point of ST-segment resolution was significantly improved with pre-
hospital administration of ticagrelor in opiate-naïve patients. These
findings challenge current guidance to administer analgesia early, on
first medical contact.27
Methods to Enhance Platelet Inhibition
Studies to overcome the potential delay in platelet inhibition, associated
with immediate pre-procedural loading of oral antiplatelet therapy,
have been undertaken. The ATLANTIC investigators addressed this
question by randomising 1,862 patients presenting within 6 hours
of STEMI onset to pre-hospital versus in-hospital treatment with
ticagrelor.34
Pre-hospital ticagrelor did not improve pre-PCI coronary
perfusion but appeared to be safe and was associated with a reduction
in post-procedural AST. The median time between the two loading
doses (pre-hospital versus in-hospital) was 31 minutes.
Alternatives to upstream administration of an oral antiplatelet therapy
include manipulation of the pharmacokinetic properties of oral
agents or use of an intravenous platelet inhibitor. The Mashed Or
Just Integral Tablets of ticagrelOr (MOJITO) study35
tested the effect of
crushing ticagrelor to accelerate drug absorption and demonstrated
a significant enhancement of platelet inhibition 1 hour following
drug ingestion. A larger scale trial with clinical endpoints would be
necessary to validate these results. Cangrelor is an intravenous
adenosine triphosphate (ATP) analogue, which reversibly inhibits the
P2Y12 receptor without requiring hepatic conversion.36
The attraction
of cangrelor is therefore its very rapid onset of action and short half-
life (3–5 minutes) allowing rapid platelet inhibition and quick reversal.
Two early trials (Cangrelor versus standard therapy to achieve optimal
management of platelet inhibition [CHAMPION]-PCI37
and CHAMPION-
PLATFORM38
) evaluating cangrelor in patients undergoing PCI failed
to show clinical superiority over clopidogrel. The more recent
CHAMPION-PHOENIX39
trial randomised 11,145 patients undergoing
urgent or elective PCI to intravenous cangrelor or clopidogrel 600
or 300 mg loading (56 % stable angina/18 % STEMI). At 48 hours the
rate of composite primary efficacy endpoint (death, MI, ischaemia-
driven revascularisation or stent thrombosis) occurred less in the
cangrelor group (4.7 % versus 5.9 %) and the rate of stent thrombosis
was significantly lower (0.8 % cangrelor versus 1.4 % clopidogrel).
Although the study demonstrated benefit with use of cangrelor, there
were significant limitations in the trial design, favouring the study drug
arm. The control group only received clopidogrel once the anatomy
was delineated, and 30 % of the cohort were administered the drug
post-PCI. Consequently, the higher rate of peri-procedural MI in the
control group is not surprising.
Antiplatelet Strategies in Patients on
Oral Anticoagulation
A significant proportion of patients undergoing PPCI may already be
anticoagulated on a vitamin K antagonist (VKA) or a non-vitamin K
antagonist oral anticoagulants ((N)OAC) at the time of the procedure.
These patients are at increased risk of bleeding and often the
international normalized ratio (INR) levels are not available. There is
no clear evidence on the optimal antithrombotic pharmacotherapy
for these patients. The 2014 ESC/EACTS guidelines on myocardial
revascularisation1
recommends that PPCI in this setting should be
Johnson_FINAL.indd 29 26/02/2015 22:12
5. Coronary Adjunctive Pharmacotherapy
INT ERVENT IONAL CARDIOLOGY REVIEW30
1. Authors/Task Force Members, Windecker S, Kolh P, et al.,
The Task Force on Myocardial Revascularization of the
European Society of Cardiology (ESC) and the European
Association for Cardio-Thoracic Surgery (EACTS) developed
with the special contribution of the European Association of
Percutaneous Cardiovascular Interventions (EAPCI), Eur Heart J,
2014;35:2541–619.
2. Randomised trial of intravenous streptokinase, oral aspirin,
both, or neither among 17,187 cases of suspected acute
myocardial infarction: ISIS-2, Lancet, 1988;332:349–60.
3. Sagar KA, Smyth MR, A comparative bioavailability study of
different aspirin formulations using on-line multidimensional
chromatography, J Pharm Biomed Anal, 1999;21:383–92.
4. O’Gara PT, Kushner FG, Ascheim DD, et al.; American College
of Cardiology Foundation/American Heart Association Task
Force on Practice G, 2013 ACCF/AHA guideline for the
management of ST-elevation myocardial infarction: a report
of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines,
Circulation, 2013;127:e362–425.
5. Mega JL, Close SL, Wiviott SD, et al., Cytochrome p-450
polymorphisms and response to clopidogrel, N Engl J Med,
2009;360:354–62.
6. Mehta SR, Yusuf S, Peters RJ, et al.; Clopidogrel in
Unstable angina to prevent Recurrent Events trial I, Effects
of pretreatment with clopidogrel and aspirin followed by
long-term therapy in patients undergoing percutaneous
coronary intervention: the PCI-CURE study, Lancet,
2001;358:527–33.
7. Sabatine MS, Cannon CP, Gibson CM, et al.; Clopidogrel
as Adjunctive Reperfusion Therapy-Thrombolysis in
Myocardial Infarction I, Effect of clopidogrel pretreatment
before percutaneous coronary intervention in patients with
ST-elevation myocardial infarction treated with fibrinolytics:
the PCI-CLARITY study, JAMA, 2005;294:1224–32.
8. von Beckerath N, Taubert D, Pogatsa-Murray G, et al.,
Absorption, metabolization, and antiplatelet effects of 300-,
600-, and 900-mg loading doses of clopidogrel: results of
the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic
Regimen: Choose Between 3 High Oral Doses for Immediate
Clopidogrel Effect) Trial, Circulation, 2005;112:2946–50.
9. Patti G, Barczi G, Orlic D, et al., Outcome comparison of
600- and 300- mg loading doses of clopidogrel in patients
undergoing primary percutaneous coronary intervention for
ST-segment elevation myocardial infarction: results from
the ARMYDA-6 MI (Antiplatelet therapy for Reduction of
MYocardial Damage during Angioplasty-Myocardial Infarction)
randomized study, J Am Coll Cardiol, 2011;58:1592–9.
10. Mehta SR, Tanguay JF, Eikelboom JW, et al., Double-dose
versus standard-dose clopidogrel and high-dose versus low-
dose aspirin in individuals undergoing percutaneous coronary
intervention for acute coronary syndromes (CURRENT-OASIS
7): a randomised factorial trial, Lancet, 2010;376:1233–43.
11. Dangas G, Mehran R, Guagliumi G, et al., Role of clopidogrel
loading dose in patients with ST-segment elevation
myocardial infarction undergoing primary angioplasty:
results from the HORIZONS-AMI (harmonizing outcomes with
revascularization and stents in acute myocardial infarction)
trial, J Am Coll Cardiol, 2009;54:1438–46.
12. Brandt JT, Payne CD, Wiviott SD, et al., A comparison of
prasugrel and clopidogrel loading doses on platelet function:
magnitude of platelet inhibition is related to active metabolite
formation, Am Heart J, 2007;153:66 e9–16.
13. Grosdidier C, Quilici J, Loosveld M, et al., Effect of CYP2C19*2
and *17 Genetic Variants on Platelet Response to Clopidogrel
and Prasugrel Maintenance Dose and Relation to Bleeding
Complications, Am J Cardiol, 2013;111:985–90.
14. Wiviott SD, Braunwald E, McCabe CH, et al., Prasugrel
versus clopidogrel in patients with acute coronary
syndromes, N Engl J Med, 2007;357:2001–15.
15. Montalescot G, Wiviott SD, Braunwald E, et al., Prasugrel
compared with clopidogrel in patients undergoing
percutaneous coronary intervention for ST-elevation
myocardial infarction (TRITON-TIMI 38): double-blind,
randomised controlled trial, Lancet, 2009;373:723–31.
16. Capodanno D, Dharmashankar K, Angiolillo DJ, Mechanism
of action and clinical development of ticagrelor, a novel
platelet ADP P2Y12 receptor antagonist, Expert Rev Cardiovasc
Ther, 2010;8:151–8.
17. Wallentin L, Becker RC, Budaj A, et al.,Ticagrelor versus
clopidogrel in patients with acute coronary syndromes,
N Engl J Med, 2009;361:1045–57.
18. Storey RF, Becker RC, Harrington RA, et al., Characterization
of dyspnoea in PLATO study patients treated with ticagrelor
or clopidogrel and its association with clinical outcomes,
Eur Heart J, 2011;32:2945–53.
19. Gaubert M, Laine M, Richard T, et al., Effect of ticagrelor-
related dyspnea on compliance with therapy in acute
coronary syndrome patients, Int J Cardiol, 2014;173:120–1.
20. Stone GW, Grines CL, Cox DA, et al., Comparison of
angioplasty with stenting, with or without abciximab, in
acute myocardial infarction, N Engl J Med, 2002;346:957–66.
21. Montalescot G, Barragan P, Wittenberg O, et al.,
Platelet glycoprotein IIb/IIIa inhibition with coronary
stenting for acute myocardial infarction, N Engl J Med,
2001;344:1895–903.
22. Ellis SG, Tendera M, de Belder MA, et al., Facilitated PCI in
patients with ST-elevation myocardial infarction, N Engl J Med,
2008;358:2205–17.
23. De Luca G, Navarese E, Marino P, Risk profile and benefits
from Gp IIb-IIIa inhibitors among patients with ST-segment
elevation myocardial infarction treated with primary
angioplasty: a meta-regression analysis of randomized trials,
Eur Heart J, 2009;30:2705–13.
24. Herrmann HC, Lu J, Brodie BR, et al., Benefit of facilitated
percutaneous coronary intervention in high-risk ST-segment
elevation myocardial infarction patients presenting to
nonpercutaneous coronary intervention hospitals, JACC
Cardiovasc Interv, 2009;2:917–24.
25. ten Berg JM, van’t Hof AW, Dill T, et al., Effect of early,
pre-hospital initiation of high bolus dose tirofiban in
patients with ST-segment elevation myocardial infarction
on short- and long-term clinical outcome, J Am Coll Cardiol,
2010;55:2446–55.
26. Stone GW, Witzenbichler B, Guagliumi G, et al., Bivalirudin
during primary PCI in acute myocardial infarction, N Engl J
Med, 2008;358:2218–30.
27. Task Force on the management of STseamiotESoC, Steg PG,
James SK, et al., ESC Guidelines for the management of acute
myocardial infarction in patients presenting with ST-segment
elevation, Eur Heart J, 2012;33:2569–619.
28. Steg PG, van ‘t Hof A, Hamm CW, et al., Bivalirudin started
during emergency transport for primary PCI, N Engl J Med,
2013;369:2207–17.
29. Shahzad A, Kemp I, Mars C, et al., Unfractionated heparin
versus bivalirudin in primary percutaneous coronary
intervention (HEAT-PPCI): an open-label, single centre,
randomised controlled trial, Lancet, 2014;384:1849–58.
30. Robson R, The use of bivalirudin in patients with renal
impairment, J Invasive Cardiol, 2000;12 Suppl. F:33F-6.
31. Parodi G, Valenti R, Bellandi B, et al., Comparison of
prasugrel and ticagrelor loading doses in ST-segment
elevation myocardial infarction patients: RAPID (Rapid
Activity of Platelet Inhibitor Drugs) primary PCI study,
J Am Coll Cardiol, 2013;61:1601–6.
32. Hobl EL, Stimpfl T, Ebner J, et al., Morphine decreases
clopidogrel concentrations and effects: a randomized,
double-blind, placebo-controlled trial, J Am Coll Cardiol,
2014;63:630–5.
33. Parodi G, Bellandi B, Xanthopoulou I, et al., Morphine is
associated with a delayed activity of oral antiplatelet agents
in patients with ST-elevation acute myocardial infarction
undergoing primary percutaneous coronary intervention,
Circ Cardiovasc Interv, 2015;8.
performed via a radial approach with use of additional parenteral
anticoagulation regardless of the timing of the last dose of oral
anticoagulant. Bivalirudin may be preferred due to its short half-life and
should be discontinued immediately after PPCI. GPIs should generally be
avoided unless for bail-out situations.
Duration of Dual Antiplatelet Therapy post-PPCI
DAPT (aspirin + a P2Y12 inhibitor) is recommended for 1 year in patients
undergoing PPCI for STEMI. This recommendation is based on the early
CURE study40
(clopidogrel) and is supported by more recent results from
TRITON-TIMI 38 (Prasugrel)15
and PLATO (Ticagrelor).17
Regardless of stent
type, extended DAPT for 1 year reduces the risk of stent thrombosis,
re-infarction and cardiovascular mortality6
with the more potent DAPTs
associated with the greatest post-ACS clinical benefit.41
Recent data
have highlighted that extended DAPT confers further protection against
ischaemic events but at the expense of additional bleeding risk.42
In stark
contrast, the Global-Leaders trial (NCT01813435) is currently enrolling
patients to either 1 month DAPT with aspirin and ticagrelor, and then
ticagrelor monotherapy for 23 month or 12 months DAPT with aspirin
and ticagrelor/clopidogrel with aspirin monotherapy between 12 and 24
months. We await the results with interest.
Antiplatelet Therapy after PCI in Patients
Requiring Oral Anticoagulation
A proportion of patients on DAPT post-PPCI will have a firm indication
for long-term anticoagulation (atrial fibrillation with Cardiac failure,
Hypertension, Age ≥75 [Doubled], Diabetes, Stroke [Doubled] –
Vascular disease, Age 65 – 74 and Sex category [Female]) [CHA2
DS2
-
VASc] score ≥2, venous thromboembolism, left ventricular [LV]
thrombus, mechanical valve prosthesis). Triple therapy with an oral
anticoagulant, aspirin 75–100 mg and clopidogrel 75 mg should be
limited in duration depending on the clinical setting, thromboembolic
risk (CHA2DS2-VASc score) and bleeding risk (HAS-BLED score). The
WOEST trial43
, which randomised 573 patients either to dual therapy
or triple therapy, showed that in patients on oral anticoagulants the
use of clopidogrel without aspirin was safe. TIMI bleeding and all-
cause mortality was lower in the dual therapy group with no increase
in the rate of thrombotic events. The 2014 ESC/EACTS guidelines on
myocardial revascularisation1
recommends 1 month of triple therapy
for ACS patients at high bleeding risk (HAS-BLED 3) and 6 months
for patients at lower bleeding risk, followed by dual therapy (oral
anticoagulant and clopidogrel or aspirin) for a minimum of 12 months
(see Table 1). The use of prasugrel and ticagrelor as part of triple
therapy should be avoided44
and gastric protection with a proton
pump inhibitor should be implemented.
Conclusion
Successful revascularisation of patients presenting with STEMI requires
rapid transfer to a PCI capable unit and concomitant treatment with
antiplatelet and antithrombotic drugs. A delicate balance exists
between thrombosis and bleeding and a perfect combination of agents
is yet to be found. An intimate relationship between the intravenous
antithrombotic and oral antiplatelet agents exists and these must be
considered in the selection/tailoring of treatment. Oral antiplatelet
therapies provide long-term platelet inhibition but are hampered by
delayed onset of action in acutely unwell patients. Future strategies
may include upstream administration of drugs by the first medical
contact or acute treatment with an intravenous platelet inhibitor. n
Johnson_FINAL.indd 30 26/02/2015 22:12
6. Contemporary Antiplatelet Strategies in the Treatment of STEMI using PPCI
INTERVENTIONAL C ARDIO LO G Y REVIEW 31
34. Montalescot G, van ‘t Hof AW, Lapostolle F, et al.,
Prehospital ticagrelor in ST-segment elevation myocardial
infarction, N Engl J Med, 2014;371:1016–27.
35. Parodi G, Xanthopoulou I, Bellandi B, et al., Ticagrelor
crushed tablets administration in STEMI patients: The
Mashed Or Just Integral Tablets of ticagrelOr (MOJITO) study,
Eur Heart J, 2014;35(Suppl.):1030.
36. Ferreiro JL, Ueno M, Angiolillo DJ, Cangrelor: a review on its
mechanism of action and clinical development, Expert Rev
Cardiovasc Ther, 2009;7:1195–201.
37. Harrington RA, Stone GW, McNulty S, et al., Platelet
inhibition with cangrelor in patients undergoing PCI,
N Engl J Med, 2009;361:2318–29.
38. Bhatt DL, Lincoff AM, Gibson CM, et al., Intravenous
platelet blockade with cangrelor during PCI, N Engl J Med,
2009;361:2330–41.
39. Bhatt DL, Stone GW, Mahaffey KW, et al., Effect of platelet
inhibition with cangrelor during PCI on ischemic events,
N Engl J Med, 2013;368:1303–13.
40. Yusuf S, Zhao F, Mehta SR, et al., Effects of clopidogrel
in addition to aspirin in patients with acute coronary
syndromes without ST-segment elevation, N Engl J Med,
2001;345:494–502.
41. Bellemain-Appaix A, Brieger D, Beygui F, et al., New P2Y12
inhibitors versus clopidogrel in percutaneous coronary
intervention: a meta-analysis, J Am Coll Cardiol, 2010;56:1542–51.
42. Mauri L, Kereiakes DJ, Yeh RW, et al., Twelve or 30 months
of dual antiplatelet therapy after drug-eluting stents,
N Engl J Med, 2014;371:2155–66.
43. Dewilde WJ, Oirbans T, Verheugt FW, et al., Use of
clopidogrel with or without aspirin in patients taking oral
anticoagulant therapy and undergoing percutaneous
coronary intervention: an open-label, randomised,
controlled trial, Lancet, 2013;381:1107–15.
44. Sarafoff N, Martischnig A, Wealer J, et al., Triple therapy
with aspirin, prasugrel, and vitamin K antagonists in
patients with drug-eluting stent implantation and an
indication for oral anticoagulation, J Am Coll Cardiol,
2013;61:2060–6.
Johnson_FINAL.indd 31 26/02/2015 22:12