Although substantial advances have been achievedin the acute management of MI and improved

early survival, there remains a risk of approximatelyone in five for death or further MI within five yearsof hospital discharge.1 Most deaths in the first fiveyears are after hospital discharge – 68 per cent forST segment elevation MI (STEMI), 86 per cent for non-ST segment elevation MI (non-STEMI)1 –and hence secondary prevention is of critical importance.

This review outlines the scope of pharmacologicalmanagement in secondary prevention of MI andhighlights the key large-scale trials that have formedthe evidence base for national and internationalguidelines.

The role of cardiac rehabilitation and lifestylemeasures is of critical importance but is beyond thescope of this review.

Antiplatelets AspirinAspirin acts primarily by cyclo-oxygenase inhibition(see Figure 1) and has been tested extensively in bothprimary and secondary prevention trials. A systematicreview of 135 000 patients compared antiplatelet ther-apy versus control in secondary prevention, andaspirin reduced the risk of vascular events (nonfatalMI, nonfatal stroke and vascular death) in patientswith previous MI (NNT=28 for two years) and acuteMI (NNT=27 for one month).2

In a further systematic review of six randomised tri-als in 6300 patients with a history of MI or cerebrovas-cular event, there was an 18 per cent (relative risk –RR 0.82, 95% CI 0.70–0.99) reduction in all-cause mor-tality (NNT=67) and a 30 per cent (RR 0.70, 95% CI0.60–0.80) reduction in vascular events (NNT=19)with an increased risk of bleeding (NNH=100).3

www.prescriber.co.uk Prescriber 19 February 2013 23

Drug review CHD

Secondary prevention of MI:

current approaches to treatmentAnoop Shah MRCP and Keith Fox FRCP

The cornerstones of second-

ary prevention of MI are drug

therapy, cardiac rehabilita-

tion and lifestyle measures.

Our Drug review considers

the mode of action and

evidence base for the wide

range of drugs available, fol-

lowed by sources of further

information.

SP

L

CPD questions available for this article. See page 29

The dosage of aspirin in secondary prevention isdebated. The Clopidogrel and Aspirin Optimal DoseUsage to Reduce Recurrent Events – SeventhOrganization to Assess Strategies in IschemicSyndromes (CURRENT-OASIS 7) trial failed to showimproved clinical efficacy with high- (300–325mg perday) compared to low-dose (75–100mg) aspirin. Therewere fewer GI bleeds in patients on low-dose aspirinand current ESC guidelines recommend low-doseaspirin for long-term secondary prevention.4

Further data from the Harmonizing Outcomeswith Revascularization and Stents in Acute MyocardialInfarction (HORIZONS-AMI) trial, investigatingpatients with STEMI treated with percutaneous coro-nary intervention (PCI), showed that high-dose aspirinwas associated with major bleeding with no beneficialeffect on ischaemic events.5

ClopidogrelClopidogrel reduces platelet activity by adenosinediphosphate receptor blockade (see Figure 1) and hasbeen tested in both non-STEMI and STEMI patients.Comparing dual therapy to aspirin alone, a systematicreview involving three trial groups – Clopidogrel inUnstable Angina to Prevent Recurrent Events

(CURE), Clopidogrel and Metoprolol in MyocardialInfarction Trial (COMMIT) and Clopidogrel asAdjunctive Reperfusion Therapy (CLARITY)6 –showed a 1.2 per cent absolute reduction in the com-posite end-point for death, stroke or MI from 10.4 to9.2 per cent (NNT=86).7

The CURE study compared clopidogrel plusaspirin versus placebo plus aspirin in patients with non-STEMI.8 The COMMIT study compared clopidogrelversus placebo in addition to aspirin in patients pri-marily presenting with STEMI.9 There was a significant1 per cent increase in the risk of major bleeding(NNH=100) in the CURE cohort but no difference infatal bleeding in COMMIT.

Newer antiplatelet agentsTwo new platelet receptor antagonists, prasugrel(Efient) and ticagrelor (Brilique), have been testedand approved as both showed improved outcomescompared with clopidogrel in the context of acutecoronary syndromes (ACS). Clopidogrel and prasu -grel are prodrugs of active metabolites and bind irre-versibly to P2Y12 platelet receptors in contrast toticagrelor, which acts directly (see Figure 1).

The Trial to Assess Improvement in TherapeuticOutcomes by Optimizing Platelet Inhibition withPrasugrel – Thrombolysis in Myocardial Infarction(TRITON-TIMI 38) trial randomised patients withACS undergoing PCI to prasugrel (60mg followed by10mg once daily) or clopidogrel (300mg followed by75mg once daily). The study showed a 1 per cent (1.4vs 2.4 per cent) reduction in cardiovascular mortality(NNT=100) and a 2 per cent (4.9 vs 7 per cent) reduc-tion in recurrent MI (NNT=48) at 30 days in the pra-sugrel group but with an increased in risk of bothlife-threatening and fatal bleeding.10 The TRITON-TIMI 38 study, however, only included patients sched-uled for PCI and the randomised intervention wasapplied only after coronary anatomy had been defined(predominantly in the catheterisation laboratory).

A more recent study – Targeted Platelet Inhibitionto Clarify the Optimal Strategy to Medically ManageAcute Coronary Syndromes (TRILOGY ACS) – ran-domised patients after ACS to clopidogrel or prasug-rel, on top of aspirin 75mg, in patients withnon-STEMI not suitable for PCI or bypass surgery.There was no overall benefit with prasugrel over clopi-dogrel (cardiovascular mortality, recurrent MI orstroke) and similar rates of bleeding.11

The Study of Platelet Inhibition and PatientOutcomes (PLATO) randomised patients with ACSto ticagrelor (180mg loading followed by 90mg twicedaily) or clopidogrel (300–600mg loading dose

24 Prescriber 19 February 2013 www.prescriber.co.uk

CHD

Figure 1. Mechanism of action of antiplatelet agents used in acute coronary

syndrome. Aspirin reduces prostaglandin formation by inhibiting cyclo-oxygenase,

clopidogrel and prasugrel indirectly inhibit and ticagrelor directly inhibits the P2Y12

platelet receptor

arachidonic acid

cyclo-oxygenase++

+

+

-

prostaglandins

thromboxane A2

platelet aggregation

and activation

prodrugs

activemetabolite-

-adenosine

diphosphate

GP IIa/IIIb receptor

P2Y12 receptor

+

+

aspirin

clopidogrel

prasugrel

ticagrelor

followed by 75mg daily). The randomised treatmentwas applied at presentation. At 12 months there wasa significant reduction in cardiovascular death (3.4 vs4.3 per cent, NNT=111) and MI (5.3 vs 6.6 per cent,NNT=77) with no significant differences in rates ofmajor bleeding (although increased non-CABGbleeding).12

Heart rate-limiting agentsBeta-blockersSubstantial evidence supports the use of beta-blockadein patients with STEMI, but the evidence largely pre-dates current reperfusion therapies and pharmaco -therapy. The beneficial effects seen in ACS patientsare likely to be driven by several mechanisms includingreduced sympathetic drive and risk of malignantarrhythmias, improved rate control and diastolic coro-nary perfusion and reduced blood pressure and car-diac afterload.

Secondary prevention with beta-blockers remainscontroversial. Based on a systematic review of 82 ran-domised clinical trials in over 50 000 patients with acuteor prior MI, beta-blockers reduced risk of death by 23per cent (NNT=42 for two years) in 31 of the trials withextended follow-up. There was, however, no mortalitybenefit in the remaining 51 short-term trials.13

Current ESC guidelines advocate beta-blockade inall STEMI patients without contraindications and inpatients with non-STEMI and evidence of depressedleft ventricular function.14,15

Calcium-channel blockersCurrent guidelines do not advocate prophylactic useof calcium-channel blockers in the acute phase of MIand there is a trend towards harm.14,15 In the chronicphase verapamil may be helpful to prevent reinfarctionand death. Rate-limiting calcium-channel blockers area reasonable (but less evidence-based) option in

26 Prescriber 19 February 2013 www.prescriber.co.uk

CHD

Table 1. Treatment recommendations from ESC guidelines

• dual antiplatelet therapy with P2Y12 inhibitor (ticagrelor

or prasugrel) added to aspirin is recommended for 12

months

• clopidogrel is recommended for patients unable to

receive ticagrelor or prasugrel

• in patients with a previous MI (>12 months) aspirin is

recommended for secondary prevention, indefinitely

• oral treatment with beta-blockers is recommended in

patients with heart failure or depressed left ventricular

function

• ACE inhibitors should be considered in all patients

especially in co-existing heart failure, left ventricular

systolic function, STEMI or diabetes

• statin therapy with a target LDL concentration of

<1.8mmol per litre initiated early after admission

Antiplatelet therapy

Beta-blockers, ACE inhibitors and lipid-lowering

therapy

Figure 2. Mechanism of action of ACE inhibitors and ARBs on the renin-angiotensin-aldosterone system

angiotensin converting

enzyme (ACE)

angiotensinogen angiotensin I angiotensin II

renin

increased sympathetic

nervous activity

increased

vasoconstriction

increased salt and

water retention

increased aldosterone

+

+

+

+

+

++

-

-

ACE inhibitors

angiotensin-II

receptor blockers

patients where beta-blockers are contraindicated ornot tolerated.14,15

Renin-angiotensin-aldosterone axis(RAAS)The primary aim of RAAS modulators is to inhibitangiotensin-II, facilitating reduction of both afterloadand preload and hence reducing myocardial strain(see Figure 2). In addition angiotensin-II inhibitionexerts positive effects on post-infarct remodelling andthese agents are specifically beneficial in patients withdepressed left ventricular function. ACE inhibitorsshould be used in all post-STEMI patients withdepressed left ventricular function, hypertension, dia-betes or chronic kidney disease. Patients intolerant ofACE inhibitors should be switched to angiotensin-IIreceptor blockers (ARBs).16

ACE inhibitors reduce death, recurrent MI andheart failure admissions in patients with coronaryartery disease with and without depressed left ventric-ular function, although efficacy varies across trials. TheHeart Outcomes Prevention Evaluation (HOPE) trialrandomised over 9000 patients with vascular disease(identified as coronary artery disease, stroke orperipheral vascular disease) to ramipril 10mg vsplacebo and showed a 3.6 per cent (14.1 vs 17.7 percent) reduction in a composite end-point of cardio-vascular death, MI or stroke (NNT=28).17

One placebo-controlled systematic review combin-ing three studies with over 5000 postinfarction patientswith depressed left ventricular function showed areduction in mortality (23.4 vs 29.1 per cent, NNT=18)and reinfarction (10.8 vs 13.2 per cent, NNT=42).18

The evidence for the use of ACE inhibitors or ARBsin patients with preserved left ventricular function isless robust for reduction in all-cause mortality(NNT=66–209) or reinfarction (NNT=62–278).19

An ARB should be used if ACE inhibitors are nottolerated (primarily due to side-effects such as coughor angioedema).

Lipid-lowering therapyStatinsStatins inhibit HMG-CoA reductase preventing thehepatocytic conversion of acetyl-CoA into cholesterol(see Figure 3). The benefits of statin therapy in sec-ondary prevention are unequivocal. A meta-analysisof 19 placebo-controlled trials in patients with coro-nary artery disease showed a 25 per cent reduction incoronary death or nonfatal MI.20

The Medical Research Council/British HeartFoundation (MRC/BHF) Heart Protection Study ran-domised over 20 000 patients, the majority of them

with underlying coronary disease or previous MI, toplacebo or simvastatin 40mg. The study showed a 12and 17 per cent reduction in all-cause mortality(NNT=57) and cardiovascular mortality (NNT=85)respectively. There was a 26 per cent reduction in anymajor coronary event (NNT=33).21

A systematic review of 8000 ACS patients with two-year follow-up evidence suggests that intensive is moreefficacious that moderate lipid-lowering statin therapy(all-cause mortality 3.5 vs 8.9 per cent respectively,NNT=19),22 mostly evident for atorvastatin23–25 withsome evidence for high-dose simvastatin.26

Statins are usually well tolerated but myalgia is fre-quently reported (although in clinical trials statinshave not been shown to significantly increase risk ofmyalgia compared to placebo).27 Rarely statins caninduce rhabdomyolysis. Occasionally they also causeliver dysfunction and should be used cautiously inpatients with chronic liver disease and those with alco-hol dependence. Liver function should be monitoredprior to commencement of statins and three monthsafter initiation. Following this, liver function shouldbe checked biannually.

Cholesteryl ester transfer protein inhibitorsMore recently cholesteryl ester transfer protein(CETP) inhibitors (not currently available in the UK)

www.prescriber.co.uk Prescriber 19 February 2013 27

CHD

Figure 3. Lipid-lowering therapies: statins inhibit the hepatic synthesis of cholesterol,

and cholesteryl ester transfer protein (CETP) inhibitors reduce LDL and increase HDL

cholesteryl

ester transfer

proteinLDL

VLDL

HDLcholesterol

cholesterol

HMG CoA

reductase

acetyl Co-A

hepatocytic

cholesterol

biosynthesisplasma

extrahepatic

tissues

+

-

-

CETP

inhibitors

statins

have been tested but with mixed results. They inhibitplasma CETP, which exchanges triglycerides fromplasma VLDL and LDL for cholesterol esters fromHDL, resulting in raised HDL concentrations andlower LDL concentrations (see Figure 3).

The Determining the Efficacy and Tolerability ofCETP Inhibition with Anacetrapib (DEFINE) trial ran-domised over 1500 patients with coronary heart dis-ease and taking a statin to either anacetrapib orplacebo. Anacetrapib reduced LDL by a further 40 percent and nearly tripled HDL levels. There was, how-ever, no difference in the composite cardiovascularend-point, although the study was not adequately pow-ered for death or MI.28 Similar results were noted fordalcetrapib, in the dal-OUTCOMES trial, which wasterminated early, with a significant increase in HDLcholesterol but no reduction in risk of cardiovascularevents in patients following incident ACS.29

ConclusionThe keystones of secondary prevention after MI arepharmacological therapy, cardiac rehabilitation andlifestyle measures, especially smoking cessation.Development of new and more potent pharmacolog-ical agents has the potential to further improve mor-bidity and mortality after ACS but most gains, on apopulation basis, would be achieved with improvedadherence to secondary prevention guidelines.

The recent development of higher-sensitivity bio-markers has improved our diagnostic accuracy fordefining ACS, making secondary prevention evenmore important.30,31

Declaration of interestsNone to declare.

References1. Fox KA, et al. Eur Heart J 2010;31:2755–64.2. Antithrombotic Trialists’ Collaboration. BMJ 2002;324:71–86.3. Weisman SM, et al. Arch Intern Med 2002;162:2197–202.4. Mehta SR, et al. NEJM 2010;363:930–42.5. Yu J, et al. JACC Cardiovasc Interv 2012;5:1231–8.6. Sabatine MS, et al. NEJM 2005;352:1179–89.7. Bowry AD, et al. Am J Cardiol 2008;101:960–6.8. Yusuf S, et al. NEJM 2001;345:494–502.9. Chen ZM, et al. Lancet 2005;366:1607–21.10. Wiviott SD, et al. NEJM 2007;357:2001–15.11. Roe MT, et al. NEJM 2012;367:1297–309.12. Wallentin L, et al. NEJM 2009;361:1045–57.13. Freemantle N, et al. BMJ 1999;318:1730–7.14. Steg PG, et al. Eur Heart J 2012;33:2569–619.15. Hamm CW, et al. Eur Heart J 2011;32:2999–3054.16. Pfeffer MA, et al. NEJM 2003;349:1893–906.17. Yusuf S, et al. NEJM 2000;342:145–53.18. Flather MD, et al. Lancet 2000;355:1575–81.19. Baker WL, et al. Ann Intern Med 2009;151:861–71.20. Wilt TJ, et al. Arch Intern Med 2004;164:1427–36.21. Heart Protection Study Collaborative Group. Lancet2002;360:23–33.22. Afilalo J, et al. Heart 2007;93:914–21.23. Cannon CP, et al. NEJM 2004;350:1495–504.24. Pedersen TR, et al. JAMA 2005;294:2437–45.25. LaRosa JC, et al. NEJM 2005;352:1425–35.26. de Lemos JA, et al. JAMA 2004;292:1307–16.27. Kashani A, et al. Circulation 2006;114:2788–97.28. Cannon CP, et al. NEJM 2010;363:2406–15.29. Schwartz GG, et al. NEJM 2012;367:2089–99.30. Mills NL, et al. JAMA 2011;305:1210–6.31. Mills NL, et al. BMJ 2012;344:e1533.

Dr Shah is cardiology research fellow and Keith Fox is professor of cardiology in the BHF/University Centre forCardiovascular Science, University of Edinburgh

28 Prescriber 19 February 2013 www.prescriber.co.uk

CHD

Figure 4. Summary of pharmacological and nonpharmacological management in the secondary prevention in MI

lifestyle measures

– smoking cessation

– dietary measures

exercise-based

cardiac rehabilitation

antiplatelet therapy

beta-blockers

RAAS modulators

lipid-lowering therapy

Secondary prevention of MI

nonpharmacological

management

pharmacological

management

CHD

www.prescriber.co.uk Prescriber 19 February 2013 29

For each section, one of the statements is false – which is it?

1a. After MI, the risk of death or further MI within five years ofhospital discharge is approximately 1 in 10

1b. 68 per cent of deaths after STEMI occur within five years ofhospital discharge

1c. 86 per cent of deaths after non-STEMI occur within five yearsof hospital discharge

1d. The keystones of secondary prevention after MI are pharma-cological therapy, cardiac rehabilitation and lifestyle meas-ures, especially smoking cessation

2a. Aspirin acts primarily by cyclo-oxygenase inhibition2b. The CURRENT-OASIS 7 showed no improvement in clinical

efficacy but more gastrointestinal bleeding events with high-compared to low-dose aspirin

2c. A systematic review of secondary prevention trials showedthat aspirin reduced the risk of vascular events in patientswith previous MI and acute MI

2d. A systematic review of six randomised trials in 6300 patientswith a history of MI or cerebrovascular events showed thatthe NNH for increased risk of bleeding was 19

3a. The active metabolites of clopidogrel and prasugrel bind irreversibly to P2Y12 platelet receptors

3b. The TRILOGY ACS trial showed no difference between clopi-dogrel and prasugrel, both in combination with aspirin, incardiovascular mortality, recurrent MI or stroke in patientswith non-STEMI not suitable for PCI or bypass surgery

3c. The TRITON-TIMI 38 trial showed that clopidogrel is associ-ated with a higher risk of fatal and life-threatening bleedingthan prasugrel in patients with ACS undergoing PCI

3d. In the PLATO trial, ticagrelor reduced the incidence of cardio-vascular death and MI compared with clopidogrel at 12 months

4a. Evidence supporting the use of beta-blockade in patientswith STEMI largely predates current reperfusion therapiesand pharmacotherapy

4b. The beneficial effects of beta-blockade in ACS patients aredriven partly by reduced sympathetic drive and improveddiastolic coronary perfusion

4c. In a systematic review of randomised trials in patients with acute or prior MI, 31 trials with extended follow-upshowed that beta-blockers reduce the risk of death by 23 percent

4d. Current guidelines recommend prophylaxis with a calcium-channel blocker in the acute phase of MI

5a. ACE inhibitors and ARBs are specifically beneficial in patientswith depressed left ventricular function

5b. ACE inhibitors should be not be used in post-STEMI patientswith diabetes or chronic kidney disease

5c. The HOPE trial showed that ramipril reduced the incidence ofthe composite end-point of cardiovascular death, MI or strokeby 3.6 per cent compared with placebo in patients with vas-cular disease

5d. An ARB should be used if ACE inhibitors are not tolerated dueto cough or angioedema

6a. Statins reduce coronary death or nonfatal MI by 25 per centin patients with coronary artery disease

6b. Although myalgia is frequently reported with statins, clinicaltrials have not shown a significantly increased risk comparedwith placebo

6c. Over two years, intensive statin therapy does not reduce mor-tality by more than moderate statin therapy in patients withACS

6d. After the first three months, liver function should be checkedbiannually during treatment with a statin

CPD: Secondary prevention of MIAnswer these questions online at Prescriber.co.uk and receive acertificate of completion for your CPD portfolio. Utilise theLearning into Practice form to record how your learning has contributed to your professional development.

GuidelinesEuropean Society of Cardiology. Management of acutecoronary syndromes (ACS) in patients presenting withoutpersistent ST-segment elevation, 2011; and in patients pre-senting with ST-segment elevation, 2012.

NICE. Bivalirudin for the treatment of ST-segment elevationmyocardial infarction (STEMI). TA230. 2011.

NICE. Management of hyperglycaemia in people with

acute coronary syndromes. CG130. 2011.

NICE. MI: secondary prevention. CG48. 2007.

NICE. Prasugrel for the treatment of acute coronary syn-dromes with percutaneous coronary intervention. TA182.2009.

NICE. Ticagrelor for the treatment of acute coronary syn-dromes (ACS). TA236. 2011.

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