Secondary Prevention of ACS

This section covers secondary prevention in ACS and the roles of anticoagulant, antiplatelet and adjunctive therapy

In this section:

Anticoagulant therapy

Introduction

The routine use of single antiplatelet therapy (ASA alone) and dual antiplatelet therapy (ASA plus a P2Y12 inhibitor) significantly improve long-term outcomes for ACS patients. However, despite this, the risk of recurrent ACS remains approximately 10% per annum after an initial event,, with most of these events occurring after hospital discharge.

The benefits of dual antiplatelet therapy are clear, but the need remains to reduce the residual rate of recurrent events. Adding an anticoagulant to antiplatelet therapy is one such approach. The rationale for this combination stems from the fact that thrombi in ACS form via a dual pathway process:

  • Platelet activation
  • Thrombin generation (which persists for some time after the event). Thrombus formation entails the thrombin-mediated cleavage of fibrinogen to fibrin, with thrombin concentration dictating the ultimate fibrin structure
Anticoagulants and antiplatelets target different pathways in clot formation
Anticoagulants and antiplatelets target different pathways in clot formation
ADP, adenosine diphosphate; GP, glycoprotein

Therapeutic strategies that include antiplatelet agents alone target only one mechanism involved in clot formation; a regimen that also involves anticoagulants addresses both pathways. Early trials antiplatelet therapy with ASA and anticoagulant therapy with warfarin for the secondary prevention of ACS, showed a greater risk of bleeding despite reductions in the rate of thromboembolic events, but uptake was limited. Guidelines note that dual therapy should be considered in selected patients, such as those with AF with a CHA2DS2-VASc score ≥2, recent VTE, left ventricular thrombus or mechanical heart valve prosthesis.

Recent studies of combined anticoagulant and antiplatelet therapy

The NOACs dabigatran, apixaban and rivaroxaban have been studied for secondary prevention of ACS. To date, only low-dose rivaroxaban has shown a positive benefit–risk profile, and only in a specific subset of patients and has received regulatory approval in several countries worldwide. In the ATLAS ACS 2 TIMI 51 trial, in patients treated with standard antiplatelet therapy (thienopyridine plus ASA or ASA alone), addition of rivaroxaban 2.5 mg twice daily resulted in:

  • A significant reduction in the composite of cardiovascular death, MI and stroke over 24 months compared with antiplatelet therapy alone (9.1% vs 10.7%; hazard ratio 0.84; p=0.02)
  • A significant increase in the rate of major bleeding (1.8% vs 0.6%; hazard ratio 3.46; p<0.001) but without any significant increase in fatal ICH and fatal bleeding

In selected patients with elevated cardiac biomarkers and no history of stroke or TIA, rivaroxaban 2.5 mg twice daily led to:

  • A similar rate of fatal bleeding to antiplatelets alone (0.1% vs 0.3%)
  • Significantly reduced cardiovascular mortality and all-cause death (by 45% and 42%, respectively)

Based on this, rivaroxaban 2.5 mg twice daily has been approved in Europe (but not in the US) as an adjunct to standard antiplatelet therapy with thienopyridine plus ASA or ASA alone, for prevention of atherothrombotic events in patients who have experienced a recent ACS event and have elevated cardiac biomarkers and no history of stroke or TIA.

Risk factors for bleeding

The benefits of adding an anticoagulant to antiplatelet therapy in the secondary prevention of ACS must be balanced against the associated increased risk of bleeding. Risk stratification schemes that can identify patients at increased risk of bleeding events are, therefore, useful in clinical decision making.

Several risk stratification schemes for evaluation of short-term bleeding risks in patients with ACS have been developed from registry or trial cohorts. These include the CRUSADE and ACTION bleeding risk scores and a score developed by Mehran et al. based on data from the ACUITY and HORIZONS trials; female sex, renal impairment and anaemia are common to the three systems. Both the CRUSADE and ACTION bleeding risk scores predict in-hospital major bleeding; scores of ≤20, 21–30, 31–40, 41–50 and >50 are indicative of very low, low, moderate, high and very high bleeding risks. The Mehran et al. bleeding risk score predicts 30-day non-coronary artery bypass bleeding; patients with scores of <10, 10–14, 15–19 and ≥20 are classified as low, moderate, high and very high risk of bleeding. Compared with the HAS-BLED scoring system to assess bleeding risk in patients with AF, the ACS bleeding risk scoring systems are less extensively validated.

Risk stratification schemes for evaluation of short-term bleeding risks in patients with ACS
CRUSADE (2009) Mehran et al. (2010) ACTION (2011)
Derivation cohort 71,277 community-treated NSTEMI patients 13,819 patients with UA or NSTEMI enrolled in the ACUITY trial and 3602 patients with STEMI enrolled in the HORIZONS-AMI trial 72,313 patients with STEMI or NSTEMI admitted to hospitals participating in the ACTION registry
Validation cohort 17,857 patients 17,960 patients
Category Variable Score Variable Score Variable Score
Sex Male
Female
0
8
Male
Female
0
8
Male
Female
0
4
Baseline renal function CrCl (ml/min)
≤15
>15–30
>30–60
>60–90
>90–120
>120


39
35
28
17
7
0
SCr (mg/dl)
<1.0
1.0–1.19
1.2–1.39
1.4–1.59
1.6–1.79
1.8–1.99
>2.0

0
2
3
5
6
8
10
SCr (mg/dl)
<0.8
0.8–1.59
1.6–1.99
2.0–2.99
3.0–3.99
4.0–4.99
5.0–5.99
≥6
On dialysis

0
1
2
4
6
8
10
11
11
Anaemic status Haematocrit (%)
<31
31–33.9
34–36.9
37–39.9
≥40


9
7
3
2
0
No anaemia
Anaemiaa
0
+6
Haemoglobin (g/dl)
<5
5–7.9
8–9.9
10–10.9
11–13.9
14–15.9
≥16


17
15
13
12
9
6
2
Signs of heart failure? No
Yes
0
7
No
Yes – HF only
Yes – HF with shock
0
3
15
Systolic blood pressure (mm Hg) ≤90
91–100
101–120
121–180
181–200
≥201
10
8
5
1
3
5
≤90
91–100
101–120
121–140
141–170
171–200
≥201
4
3
2
1
0
1
2
Prior vascular disease? No
Yesb
0
6
No
Yesc
0
3
Heart rate (bpm) <70
71–80
81–90
91–100
101–110
111–120
≥120
0
1
3
6
8
10
11
≤40
41–60
61–70
71–80
81–100
101–110
111–120
121–130
131–150
≥151
0
2
3
5
6
8
9
11
12
14
Diabetes mellitus? No
Yes
0
6
No
Yes
0
3
Age (years) <50
50–59
60–69
70–79
≥80
0
3
6
9
12
≤40
41–50
51–60
61–70
71–80
81–90
≥91
0
1
2
3
4
5
6
Antithrombotic medications Heparin + GPI
Bivalirudin monotherapy
0

–5
Prior warfarin use?
No
Yes


0
2
ACS presentation/ ECG changes STEMI
NSTEMI with raised biomarkers
NSTEMI with normal biomarkers
6

2

0
No ST changes
ST depression (or transient elevation)
ST elevation
0

3



7
Other criteria White blood cell count (109/l)
<10
10–11.99
12–13.99
14–15.99
16–17.99
18–19.99
>20



0
2
3
5
6
8
10
Body weight (kg)
≤50
51–70
71–100
101–120
121–140
≥141


5
4
3
2
1
0

aAnaemia defined as haemoglobin <13 g/dl in male patients and <12 g/dl in female patients; bprior vascular disease was defined as history of peripheral artery disease or prior stroke; cprior vascular disease was defined as previous PAD
bpm, beats per minute; GPI, glycoprotein IIb/IIIa inhibitor; SCr, serum creatinine

Antiplatelet therapy

Introduction

Activated platelets and thrombin generation persist for considerable periods after an ACS event, potentially leaving patients at risk of further ischaemic events and providing therapeutic targets for secondary prevention strategies.

Antiplatelet therapy is the cornerstone of strategies to prevent recurrent ACS:

  • ASA reduces the risk of serious vascular events in patients at increased risk, including those with prior or acute events
  • The addition of a second antiplatelet drug (e.g. clopidogrel or one of the newer P2Y12 inhibitors prasugrel and ticagrelor) to ASA has been shown to provide additional benefit
Approved antiplatelet agents for the secondary prevention of ACS
Drug Target Dose/regimen Supporting data
ASA Irreversibly inhibits the COX-­1 enzyme 75–325 mg daily Meta-analysis of 195 clinical trials
Thienopyridines Irreversibly bind to the ADP receptor P2Y12 Clopidogrel: 75 mg daily

Prasugrel:
10 mg daily
CURE (clopidogrel + ASA)

TRITON-TIMI 38 (prasugrel + ASA)

TRILOGY ACS (prasugrel vs clopidogrel)
Ticagrelor (non-thienopyridine) Reversibly binds to P2Y12, non­competitively with ADP 90 mg twice daily PLATO (ticagrelor + ASA)

ADP, adenosine diphosphate; COX-­1, cyclooxygenase-1

Guideline recommendations

All patients, unless contraindicated, should be discharged from hospital on antiplatelet therapy. Most guidelines recommend that patients should continue taking ASA indefinitely, whereas clopidogrel, prasugrel and ticagrelor should usually be given for up to 12 months after an ACS event, regardless of the initial management strategy.

Guidelines for antiplatelet therapy for the acute, sub-acute and long-term secondary prevention of ACS, indicating year of latest update
ACCP ESC ACC/AHA
Date of publication 2012 2015 2014
UA/NSTEMI
No stent ASA 75–100 mg daily PLUS ticagrelor
90 mg twice daily or clopidogrel
75 mg daily
Recommended for 12 months
After 12 months:
ASA 75–100 mg daily or clopidogrel
75 mg daily
ASA 150–300 mg loading dose then 75–100 mg daily continued long term, PLUS a P2Y12 inhibitor for 12 months; one of:
  • Ticagrelor 180 mg loading dose then 90 mg twice dailya
  • Prasugrel 60 mg loading dose then 10 mg dailyb,c
  • Clopidogrel 300–600 mg loading dose then 75 mg dailyd
ASA 162–325 mg promptly after presentation then a maintenance dose of ASA 81–162 mg daily continued indefinitely, PLUS a P2Y12 inhibitor for up to 12 months; one of:
  • Clopidogrel 300 or 600 mg loading dose then 75 mg daily
  • Ticagrelor 180 mg loading dose then 90 mg twice dailye
Bare-metal stent ASA 75–100 mg daily Ticagrelor 90 mg twice daily, clopidogrel 75 mg daily or Prasugrel 10 mg daily Recommended for 12 months, minimum 1 month After 12 months:
ASA 75–100 mg daily or clopidogrel
75 mg daily
As above ASA 162–325 mg promptly after presentation then a maintenance dose of 81–325 mg daily continued indefinitely,f PLUS a P2Y12 inhibitor for at least 12 monthsf or beyond; one of:
  • Clopidogrel 300 or 600 mg loading dose then 75 mg daily
  • Prasugrel 60 mg loading dose then 10 mg dailyc
  • Ticagrelor 180 mg loading dose then 90 mg twice dailye
Drug-eluting stent ASA 75–100 mg daily Ticagrelor 90 mg twice daily, clopidogrel 75 mg daily or prasugrel 10 mg daily
Recommended for 12 months, minimum 3–6 months
After 12 months: ASA 75–100 mg daily or clopidogrel
75 mg daily
As for bare-metal stent As for bare-metal stent
Date of publication 2012 2012 2013
STEMI
No stent As for UA/NSTEMI For patients who did not receive reperfusion therapy:
ASA 150–500 mg loading dose, then 75–100 mg daily indefinitely, PLUS clopidogrel 75 mg daily for at least 1 month and up to 12 months

For patients who underwent fibrinolysis:
ASA 150–500 mg loading dose, then 75–100 mg daily indefinitely, PLUS clopidogrel loading dose of 300 mg then
75 mg daily for up to 12 months

For patients who underwent PCI without stent placement:i
ASA 150–500 mg loading dose, then 75–100 mg daily indefinitely, PLUS a P2Y12 inhibitor for up to 12 months; one of:
  • Clopidogrel
    600 mg loading dose then 75 mg daily
  • Prasugrel 60 mg loading dose then 10 mg dailyc,j,k
  • Ticagrelor 180 mg loading dose then 90 mg twice daily

For selected patients who receive ASA and clopidogrel:
Low-dose rivaroxaban (2.5 mg twice daily) may be considered if the patient is at low risk of bleeding
For patients who underwent fibrinolysis:
ASA 162–325 mg loading dose then maintenance dose of 81–325 mg daily continued indefinitely PLUS clopidogrel loading dose of 300 mg then 75 mg daily for at least 14 days and up to 12 months

For patients who underwent PCI without stent placement – recommendations as for those listed for bare-metal stent
Bare-metal stent As for UA/NSTEMI As recommended for patients who underwent PCI without stent placement – dual antiplatelet therapy with ASA plus a P2Y12 inhibitor must be continued for up to 12 months with a strict minimum of 1 month ASA 162–325 mg loading dose then 81–325 mg daily indefinitely,f PLUS a P2Y12 inhibitor for 12 months; one of:
  • Clopidogrel 600 mg loading dose then 75 mg daily
  • Prasugrel 60 mg loading dose then 10 mg dailyc
  • Ticagrelor 180 mg loading dose then 90 mg twice dailye
Drug-eluting stent As for UA/NSTEMI As recommended for patients who underwent PCI without stent placement – dual antiplatelet therapy with ASA plus a P2Y12 inhibitor must be continued for up to 12 months with a strict minimum of 6 months As above, although treatment with P2Y12 inhibitor may be continued beyond 12 months

aTicagrelor is recommended for all patients at moderate-to-high risk of ischaemic events (e.g. elevated troponins), regardless of initial treatment strategy and including those pre-treated with clopidogrel (which should be discontinued when ticagrelor is commenced); bprasugrel is recommended for P2Y12-inhibitor-naïve patients in whom coronary anatomy is known and who are proceeding to PCI unless there is a high risk of life-threatening bleeding or other contraindications; cprasugrel is contraindicated in patients with a history of stroke or TIA; dclopidogrel is recommended for patients who cannot receive ticagrelor or prasugrel; eif ticagrelor is given, the recommended maintenance dose of ASA is 81 mg daily; fthe preferred maintenance dose of ASA is 81 mg daily; gif the risk of morbidity from bleeding outweighs the anticipated benefit of a recommended duration of P2Y12 inhibitor therapy after stent implantation, earlier discontinuation (e.g. <12 months) of P2Y12 inhibitor therapy is reasonable; ha 300 mg loading dose for patients ≤75 years of age only; for patients >75 years old a
75 mg dose should be given; ifor patients who underwent PCI dual antiplatelet therapy with ASA and prasugrel or ASA and ticagrelor is recommended over ASA and clopidogrel; jin patients with a body weight of <60 kg, a 5 mg daily maintenance dose of prasugrel is recommended; kprasugrel is not generally recommended in patients ≥75 years old, but a maintenance dose of 5 mg daily should be used if treatment is deemed necessary
ACC, American College of Cardiology; ACCP, American College of Chest Physicians; AHA, American Heart Association; ESC, European Society of Cardiology

Adjunctive therapy

The management of underlying disorders (e.g. hypertension, diabetes, dyslipidaemia) and other risk factors, through medical management and lifestyle changes, is an important part of secondary prevention strategies after ACS.

Other agents recommended for use in secondary prevention include:

  • β­-blockers – lower heart rate, blood pressure and contractility, which reduces myocardial oxygen consumption
  • ACE inhibitors – reduce ventricular remodelling and prevent further deterioration in ventricular performance in patients with reduced left ventricular systolic function after MI
  • Angiotensin receptor blockers – also reduce ventricular remodelling
  • Statins – benefits of reducing low-density lipoprotein levels with statins include plaque stabilization, restoration of endothelial function and anti-inflammatory effects
  • Aldosterone antagonists – block the activation of mineralocorticoid receptors, which has adverse effects in cardiovascular disease

Although not currently included in any guideline recommendations, vorapaxar – a protease-activated receptor (PAR-1) antagonist has been approved by the US Food and Drug Administration for prevention of atherothrombotic events, added to standard of care, in patients with a history of MI and no history of stroke/TIA. Recent positive opinion for vorapaxar from the Committee for Medicinal Products for Human Use (CHMP) has recommended an extension to the existing indication as follows:

Vorapaxar (Zontivity®, Merck) is indicated for the reduction of atherothrombotic events in adult patients with:

  • A history of MI, co-administered with ASA and, where appropriate, clopidogrel; or
  • Symptomatic PAD, co-administered with ASA or, where appropriate, clopidogrel

In addition to medical strategies, patients who have experienced an ACS event are advised to make lifestyle changes to reduce their overall cardiovascular risk, including:

  • Smoking cessation
  • Regular physical activity
  • Weight reduction in patients with high body mass index and/or large waist circumference
  • Reduction in the intake of salt and saturated fat
  • Increase in consumption of fruit, vegetables, wholegrain cereals, lean meat and fish

Next section: Coronary & Peripheral Artery Disease

Approval No.: G.MKT.GM.XA.08.2016.1047

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