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,1,2 with most of these events occurring after hospital discharge.3
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 approach4,5 The rationale for this combination stems from the fact that thrombi in ACS form via a dual pathway process:4
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.8 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).9
Recent studies of combined anticoagulant and antiplatelet therapy
The NOACs dabigatran, apixaban and rivaroxaban have been studied for secondary prevention of ACS.10-12 Only low-dose rivaroxaban has shown a positive benefit–risk profile, which was in a specific subset of patients, and has received regulatory approval in several countries worldwide.13 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:14
- 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:15
- 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.13
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.16-18 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.16,18 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.17 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.
| CRUSADE (2009)16 | Mehran et al (2010)17 | ACTION (2011)18 | ||||
|---|---|---|---|---|---|---|
| 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.6,19,20
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 4,5,9,21-24
- The addition of a second antiplatelet drug (e.g. clopidogrel or one of the newer P2Y12 inhibitors prasugrel and ticagrelor1,2) to ASA has been shown to provide additional benefit25,26
| Drug | Target | Dose/regimen | Supporting data |
|---|---|---|---|
| ASA | Irreversibly inhibits the COX1 enzyme | 75–325 mg daily | Meta-analysis of 195 clinical trials27 |
| Thienopyridines | Irreversibly bind to the ADP receptor P2Y12 | Clopidogrel: 75 mg daily Prasugrel: 10 mg daily | CURE (clopidogrel + ASA)25 TRITON-TIMI 38 (prasugrel + ASA)1 TRILOGY ACS (prasugrel vs clopidogrel)28 |
| Ticagrelor (non-thienopyridine) | Reversibly binds to P2Y12, noncompetitively with ADP | 90 mg twice daily | PLATO (ticagrelor + ASA)2 |
ADP, adenosine diphosphate; COX1, cyclooxygenase-1
Guideline recommendations
All patients, unless contraindicated, should be discharged from hospital on antiplatelet therapy.4,5,9,21-24 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.4,5,9,21-24
| ACCP | ESC | ACC/AHA | |
|---|---|---|---|
| Date of publication | 201222 | 20159 | 201424 |
| 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:
| 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:
|
| 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:
|
| 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 above | As for bare-metal stent |
| Date of publication | 201222 | 201721 | 201323 |
| STEMI | |||
| No stent | As for UA/NSTEMI | For patients who did not receive reperfusion therapy: ASA 150 – 300mg loading dose (in ASA-naïve patients) and a long-term maintenance dose of 75–100 mg daily For patients who underwent fibrinolysis: Dual antiplatelet therapy (DAPT) with ASA and clopidogrel is recommended for 1 month and up to 12 months in patients with fibrinolysis without subsequent PCI DAPT with ASA and clopidogrel is recommended for up to 12 months for patients undergoing fibrinolysis and subsequent PCI For patients who underwent PCI without stent placement:i DAPT with ASA and a P2Y12 inhibitor (ticagrelor or prasugrel or clopidogrel if ticagrelor and prasugrel are not available or are contraindicated) is recommended for up to 12 months unless there is an excessive risks of bleeding P2Y12 inhibitor for up to 12 months; one of:
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 | DAPT with ASA plus a P2Y12 inhibitor is recommended for 12 months for patients with ACS undergoing PCI where the risk of bleeding is low. In patients with an excessive risk of bleeding, 6 months DAPT with ASA plus a P2Y12 inhibitor is advised29 | ASA 162–325 mg loading dose then 81–325 mg daily indefinitely,f PLUS a P2Y12 inhibitor for 12 months; one of:
|
| Drug-eluting stent | As for UA/NSTEMI | DAPT with ASA plus a P2Y12 inhibitor is recommended for 12 months for patients with ACS undergoing PCI where the risk of bleeding is low. In patients with an excessive risk of bleeding, 6 months DAPT with ASA plus a P2Y12 inhibitor is advised29 | 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; 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:4,5,9,21,23,24
- βblockers – 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
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: 4,5,9,21,23,24
- 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
References
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See Also
Peripheral Artery Disease: causes and consequences
See Also
Coronary Artery Disease: causes and consequences
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