LMWH in ACS.pptx

ACS Management: Role of LMWH
ASHISH GUPTA

 ACS: Global and Indian Perspective
 Diagnosis (Key Aspects)
 Current management of ACS
 Anti-coagulant in ACS
 LMWH in ACS: Pharmacological consideration
 Role of LMWH in;
 Coronary intervention procedures
 STEMI
 Clinical Evidence Overview
 LMWH versus UFH
 Guideline Recommendations
 Early anticoagulation in the current management of NSTE-ACS
 LMWHs in High-Risk Subgroups
 Summary
Objectives

ACS – Global perspective
• Cardiovascular diseases (CVDs) are the leading cause of death globally.
• An estimated 17.9 million people died from CVDs in 2019, representing 32% of all global
deaths. Of these deaths, 85% were due to heart attack and stroke.
• Over three quarters of CVD deaths take place in low- and middle-income countries.
• Out of the 17 million premature deaths (under the age of 70) due to noncommunicable
diseases in 2019, 38% were caused by CVDs.
• Most cardiovascular diseases can be prevented by addressing behavioral risk factors such
as tobacco use, unhealthy diet and obesity, physical inactivity and harmful use of alcohol.
• It is important to detect cardiovascular disease as early as possible so that management with
counselling and medicines can begin.
https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

 Compared with the high-income countries, in low- and middle-income countries is
characterized by premature onset and high case fatality rate.
 In India, CVD is responsible for about 27% of all deaths.
 The age-standardized death rate from CVD in India is 272 per 100 000 population as
compared with global average of 235 per 100, 000 population.
 The mean age of presentation was 56.06 ± 11.29 years, CREATE
registry(56 ± 13 years), Jose and Gupta study (57 ± 13 years), Sharma et al
(54.70 ± 19.90 years), but less than Kerala ACS registry (60.4 ± 12.1 years).
ACS – Indian perspective

Types of acute coronary syndromes
Demirel ME, Donmez I, Uçaroğlu ER, Yüksel A (2019) Acute coronary syndromes and diagnostic methods. Med Res Innov 3: DOI: 10.15761/MRI.1000167.

Diagnostic algorithm for acute coronary syndrome
Pleister, Adam & Selemon, Helina & Elton, Shane & Elton, Terry. (2013). Circulating miRNAs: Novel biomarkers of acute coronary syndrome?. Biomarkers in medicine. 7. 287-305. 10.2217/bmm.13.8.

Key aspects in diagnosis
• Initial cardiac troponin levels provide prognostic information in terms of short- and
long-term mortality to clinical and ECG variables.
• hs-cTn T has greater prognostic accuracy. The higher the hs-cTn levels, the greater the
risk of death
• Serum creatinine and eGFR : in all patients with NSTE-ACS because they affect
prognosis
• Natriuretic peptides [BNP and N-terminal pro-BNP (NT-proBNP)] provide prognostic
information , the risk of death, acute heart failure, as well as the development of AF.
• Other biomarkers, such as high-sensitivity C-reactive protein, mid-regional pro-
adrenomedullin, growth differentiation factor 15 (GDF-15), heart-type fatty acid-binding
protein (h-FABP), and copeptin may also have some prognostic value.
• GRACE risk score predicts clinical outcomes

Diverse mechanisms causing ACS
Therapies that modify
thrombogenesis form the
foundation for the
management of ACS and
prevention of recurrent
ischemic events.
Onwordi EN, Gamal A, Zaman A. Anticoagulant Therapy for Acute Coronary Syndromes. Interv Cardiol. 2018 May;13(2):87-92. doi: 10.15420/icr.2017:26:1. PMID: 29928314; PMCID: PMC5980649.

Early mechanical and chemical
reperfusion with percutaneous
coronary intervention
Use of antithrombotic agents
ACS treatment strategy
Reduce the frequency of both early
and late cardiovascular events.
Rational of use of Anticoagulants in ACS
 Increased use of PCI necessitates adequate antithrombotic therapy to reduce the risk of
device-related complications.
 Once a decision is made for invasive management then either UFH or LMWH must
be given during catheterization to prevent formation of thrombus during the
procedure

Main
Mechanisms of
Thrombogenesis
and action of
anticoagulants

Anticoagulation Therapies
• Unfractionated Heparin
• Low Molecular Weight Heparin
• Fondaparinux
• Bivalirudin
• New anticoagulant agents including anti-Xa therapies (apixaban,
rivaroxaban, otamixaban) and the direct thrombin inhibitor dabigatran.

Current management of ACS
Guidelines recommend prompt initiation of aspirin (or a
thienopyridine if aspirin is not tolerated)
Addition of an anticoagulant agent, such as
unfractionated heparin (UFH) or low-molecular-weight
heparin (LMWH
A platelet glycoprotein (GP) IIb/IIIa receptor antagonist
should be added if ischemic pain continues or in high-
risk subjects
Clopidogrel is also recommended for patients not going
to catheterization and bypass surgery
 Main aim to prevent the
progression of
UA/NSTEMI to MI or
death.
 American College of
Cardiology/American
Heart Association
guidelines includes a
combination of
antiplatelet and
antithrombotic therapy

Determinants of antithrombotic treatment in coronary
artery disease

LMWH in ACS:
Pharmacological
consideration

The use of LMWH and UFH was
analyzed in 13,231 ACS patients,
 Patients receiving LMWH had
significantly lower rates of hospital
mortality and major bleeding
 UFH tends to be used more frequently
than LMWH, but hospital outcomes
appeared to be better with LMWH
after adjusting for covariables.

• Anti-Xa activity.
• 70% to 80% LMWH acts via mechanisms that are independent of
antithrombin
Release of tissue factor pathway inhibitor (TFPI)
interaction with heparin cofactor II, inhibition of procoagulant effects of leukocytes
promotion of fibrinolysis
protein binding
effects on vascular endothelium (receptor mediated and receptor independent)
Turpie AGG, Antman EM. Low-Molecular-Weight Heparins in the Treatment of Acute Coronary Syndromes. Arch Intern Med. 2001;161(12):1484–1490. doi:10.1001/archinte.161.12.1484

Differences in biological activities among LMWHs
 variations in affinity for coagulation proteins
 differences in binding to endothelial cells and blood cells
 differences in protease inhibition
 differences in bioavailability and pharmacokinetics.
 Molecular weights between 4000 and 8000 kd
 Differ in their ability to release endogenous TFPI
The efficacy of a given LMWH in ACS depends on interactions
between numerous biological activities like anti-Xa and anti-IIa
activities, release of TFPI, and effects on the vascular
endothelium
Turpie AGG, Antman EM. Low-Molecular-Weight Heparins in the Treatment of Acute Coronary Syndromes. Arch Intern Med. 2001;161(12):1484–1490. doi:10.1001/archinte.161.12.1484

LMWH
agents
• Enoxaparin and Dalteparin : FDA approved for
the treatment of UA/NSTEMI
• Enoxaparin : approved for the treatment of
venous thrombosis
• Tinzaparin : approved for the treatment of
venous thrombosis
• Other LMWH agents available : nadroparin,
and ardeparin

Role of LMWH in the
treatment of ACS

Enoxaparin
Most studied and utilized LMWH.
A to Z trial : Non-inferiority compared with UFH in patients with NSTE-ACS
managed with aspirin and tirofiban.
 SYNERGY trial : Enoxaparin non-inferior with respect to a composite end-
point of death and non-fatal MI at 30 days in patients presenting with high-risk
NSTE-ACS managed with an early invasive strategy.
ATOLL trial : Patients treated with enoxaparin reported significantly reduced
rates of death, recurrent ACS and urgent revascularization with no significant
increase in bleeding rates.

The Essence Trial: Efficacy and Safety of Subcutaneous Enoxaparin in Unstable
Angina and Non-Q-Wave MI
A Double-Blind, Randomized, Parallel-Group, Multicenter Study Comparing Enoxaparin and Intravenous Unfractionated
Heparin: Methods and Design
After 14 days, patients who had been treated with
enoxaparin had a significantly reduced risk of death, MI,
or recurrent angina compared to those who received
UFH.
One-year follow-up results
 reduction with enoxaparin in the incidence of the
composite end point was maintained
 Reduction in the need for diagnostic catheterization
and coronary revascularization
 reduce rebound ischemia than UFH
https://www.sciencedirect.com/science/article/pii/S0735109702029017

The Thrombolysis in Myocardial Infarction (TIMI)-11B trial
• To evaluate the safety and efficacy of subcutaneous enoxaparin compared with unfractionated
heparin for the treatment of patients presenting with unstable angina or non-Q-wave
myocardial Infarction.
• Results :
At 14 days, there was a 15% reduction in the composite end point of death, MI, or
recurrent angina with enoxaparin (14.2% vs. 16.7%; p = 0.029).
This benefit was maintained at 43 days.
The results of TIMI 11B suggest that for the acute phase of management of unstable
angina/non–Q-wave MI, antithrombin therapy with enoxaparin is superior to unfractionated
heparin.
Because the median duration of acute treatment with enoxaparin in TIMI 11 B was 4.6 days,
it seems reasonable to continue its administration throughout the initial hospitalization

Prior aspirin users
treated with
enoxaparin
Prior aspirin users
taking UFH.
Reduced rate of death, MI,
or urgent revascularization
Subanalysis of ESSENCE and TIMI-11B

Meta-analysis of LMWH trials in unstable angina/non–ST-
segment elevation myocardial infarction

ST-Elevation Myocardial Infarction &
Unstable angina/non–ST-elevation myocardial infarction
• Associated with complete
thrombotic occlusion of the
artery
ST-elevation
myocardial infarction
(STEMI)
• Associated with nonocclusive
thrombus
Unstable angina/non–
ST-elevation
myocardial infarction
(UA/NSTEMI)
Wong GC, Giugliano RP, Antman EM. Use of Low-Molecular-Weight Heparins in the Management of Acute Coronary Artery Syndromes and Percutaneous Coronary Intervention. JAMA. 2003;289(3):331–
342. doi:10.1001/jama.289.3.331

Clinical efficacy and major bleeding in trials of LMWH trials in ST-
segment elevation myocardial infarction
342. doi:10.1001/jama.289.3.331

Adjunctive LMWH in STEMI – Trials
342. doi:10.1001/jama.289.3.331
Improved late
coronary artery
patency rates
Improved tissue level
perfusion following
fibrinolysis
Reduced rates of
clinical events such
late infarct-related
arterial re-occlusion
and recurrent ischemia
with LMWH
compared

• In clinical trials comparing
low-molecular-weight
heparin with heparin,
enoxaparin sodium has
been shown to reduce the
risk of coronary events in
patients with non–ST
segment elevation acute
coronary ischemia.

Conclusion
• Subcutaneous weight-
adjusted LMWH is as
effective and safe as
intravenous UFH in the
management of patients
with acute coronary
syndromes.
• The logistic ease of
administration without
the need for monitoring
anticoagulation appears
to be the major
advantage over UFH

• Enoxaparin demonstrated
efficacy in improving clinical
outcomes in unstable
angina/NSTEMI patients
• Initial results are very
encouraging, and they indicate
that enoxaparin may potentially
substitute for UFH as
adjunctive therapy in fibrin-
specific thrombolytic regimens
and improve coronary
reperfusion rates in
streptokinase-based regimens.

Wong GC, Giugliano RP, Antman EM. Use of low-molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention. JAMA. 2003 Jan 15;289(3):331-42. doi:
10.1001/jama.289.3.331. PMID: 12525234.

Mechanisms responsible for the pharmacokinetic advantages
of LMWH versus UFH
Advantage Mechanism
More predictable anticoagulant response Less binding to plasma proteins and to
proteins released from activated platelets
and endothelial cells
Better bioavailability at low doses Less binding to endothelium
Dose-independent clearance mechanism Less binding to macrophages
Longer half-life Less binding to macrophages
N Engl J Med 1997; 337:688-698
DOI: 10.1056/NEJM199709043371007

Two Randomized trials comparing LMWH with UFH
given to patients for proximal deep vein thrombosis
Comparison of rates of recurrence of thromboembolism, major bleeding episodes and death rates
N Engl J Med 1997; 337:688-698
DOI: 10.1056/NEJM199709043371007

Potential Advantages of LMWH over UFH
Similar or superior efficacy
Similar or superior safety
Superior bioavailability
Once- or twice-daily dosing
No laboratory monitoring*†
Less phlebotomy
Subcutaneous administration*
Earlier ambulation
Home therapy in certain patient subsets
*For both prophylaxis and treatment
Tapson VF. Treatment of acute deep venous thrombosis and pulmonary embolism: use of low molecular weight heparin. InSeminars in respiratory and critical care medicine 2000 (Vol. 21, No. 06, pp. 533-540). Copyright© 2000
by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662.

Early anticoagulation
in the current
management of NSTE-
ACS

https://www.internationaljournalofcardiology.com/article/S0167-5273(18)31178-1/fulltext

Early anticoagulation in the current management of
NSTE-ACS: Evidence
• Evidence in favor of anticoagulants versus placebo in the early phase of NSTE-ACS
• ESC guidelines on NSTE-ACS strongly suggest the early use of triple ATT.
• Need of a more individualized approach to early anticoagulation in NSTE-ACS patients
taking into account the time frame of subsequent coronary angiography/ revascularization
and the specific anticoagulant to be used.
• Anticoagulant therapy during the acute phase of non-ST elevation acute coronary
syndromes (NSTE-ACS) is strongly recommended by current international
guideline
Galli M, Porto I, Andreotti F, D'Amario D, Vergallo R, Della Bona R, Crea F. Early anticoagulation in the current management of NSTE-ACS: evidence, guidelines, practice and perspectives. International Journal
of Cardiology. 2019 Jan 15;275:39-45.

Timeline of the randomized controlled trials testing early antithrombotic
regimens currently recommended by non-ST-elevation acute coronary syndromes
guidelines.
Galli M, Andreotti F, D’Amario D, Vergallo R, Vescovo GM, Giraldi L, Migliaro S, Ameri P, Porto I, Crea F. Antithrombotic therapy in the early phase of non-ST-elevation acute coronary syndromes: a systematic review and meta-
analysis. European Heart Journal-Cardiovascular Pharmacotherapy. 2020 Jan 1;6(1):43-56.

Early intravenous anticoagulation
antagonizes the
ongoing coronary
thrombosis
facilitates the
percutaneous
coronary
intervention
reduction of
mortality and
acute stent
thrombosis
reduces the
ischemic burden
Zeitouni M, Kerneis M, Nafee T, Collet JP, Silvain J, Montalescot G. Anticoagulation in acute coronary syndrome-state of the art. Progress in Cardiovascular Diseases. 2018 Jan 1;60(4-5):508-13.

The British National Formulary (BNF) and National
Institute for Health and Care Excellence (NICE)
LMWHs approved for (2022)
• DVT prophylaxis in medium and high-risk groups (surgical, orthopedic, and medical
patients)
• Treatment of venous thromboembolism in pregnancy
• Treatment of DVT and PE in nonpregnant women (those with both high and low risk of
recurrence)
• Treatment of STEMI (in both those undergoing percutaneous coronary intervention and
those not)
• Unstable angina
• Prevention of clotting in extracorporeal circuits
Solari F, Varacallo M. Low Molecular Weight Heparin (LMWH) [Updated 2022 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK525957/

Recommended anticoagulant and antiplatelet drugs for use during and
after NSTE-ACS)
Collet, J.P., Thiele, H., Barbato, E., Barthélémy, O., Bauersachs, J., Bhatt, D.L., Dendale, P., Dorobantu, M., Edvardsen, T., Folliguet, T. and Gale, C.P., 2021. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment
elevation: the Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). European heart journal, 42(14), pp.1289-1367.
Drugs with preferred parenteral administration in red

LMWH in special populations
LMWHs have superior pharmacokinetic properties as compared to UFH, including high
bioavailability, making them a desirable alternative.
Alternative dosing strategies and close monitoring are required in patients with altered
volumes of distribution, the elderly, and those with renal dysfunction.
 Obesity : Studies suggested that dosing of individual LMWHs do not need to be adjusted
for the following patients:
(1) enoxaparin if ≤144 kg
(2) dalteparin if ≤190 kg
(3) tinzaparin if ≤165 kg
Recommend enoxaparin 1 mg/kg SC BID (based on TBW) in obese patients
Malloy RJ, Rimsans J, Rhoten M, Sylvester K, Fanikos J. Unfractionated heparin and low-molecular-weight heparin. InAnticoagulation Therapy 2018 (pp. 31-57). Springer, Cham.

Renal Dysfunction and Elderly Patients
Monitoring anti-Xa levels should be considered when treating renally impaired
patients with prolonged courses of LMWH
 Guidelines support dose reduction of LMWH in patients with renal
dysfunction (CrCl<30ml/min )whether used for thromboprophylaxis or treatment
Pregnancy
LMWH, like UFH, does not cross the placenta leading to a generally low risk
of fetal bleeding
Thrombo-prophylactic dosing of enoxaparin 40 mg SC daily appears to be safe
and effective for prevention of VTE during pregnancy
Guidelines recommend that pregnant women requiring therapeutic anticoagulation
for treatment of VTE use LMWHs over UFH or vitamin K antagonists (VKA)
during the peripartum period
Malloy RJ, Rimsans J, Rhoten M, Sylvester K, Fanikos J. Unfractionated heparin and low-molecular-weight heparin. InAnticoagulation Therapy 2018 (pp. 31-57). Springer, Cham.

Conclusion
• A patient-centered approach is required to balance ischemic and bleeding risk
• Important to make a choice of antiplatelet agents of differing potency and anticoagulants limited to low
dose heparins.
• Anticoagulation in conjunction with antiplatelet therapy is central to the management of ACS.
• A backbone of anti-thrombotic therapy at presentation of patients with ACS is heparin which may be
LMWH or UFH
• LMWH offers more constant and probable anticoagulation without the need for monitoring of
activated clotting time
• Moreover, LMWH is more persuasive anticoagulant in relations to decreasing the re-infarction in
comparison to UFH.
• Choosing triple rather than dual or single ATT in the early phase on NSTE-ACS should consider the
risk/benefit ratio of each antithrombotic combination

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