Outpatient Management of Survivors of Acute Coronary Syndromes

 

Outpatient Management of Survivors of  Acute Coronary Syndromes Corona Cor onary ry art artery ery dis diseas easee (CA (CAD) D) con contin tinues ues to gro grow w in pre preval valenc encee as the incidence incid ence of athero atherosclero sclerotic tic risk facto factors rs (diab (diabetes, etes, hyper hypertensi tension, on, dysli dyslipidem pidemia) ia) escalates. Acute coronary syndromes (ACS) occur when an atherosclerotic plaque in a cor corona onary ry art artery ery rup ruptur tures, es, act activa ivatin ting g clo clott for format mation ion,, whi which ch sud sudden denly ly and critically reduces coronary blood flow. The result can be reversible myocardial ischemia, ische mia, ische ischemia mia with small amounts of myoca myocardial rdial necrosis (non-ST elevation myocardial infarction) or large areas of frank (ST elevation) myocardial infarction (MI). (M I). Ea Earl rlie ierr rec recog ogni niti tion on of AC ACS, S, ac achi hiev eved ed th throu rough gh pu publ blic ic educ educat atio ion, n, ha hass combined with more effective initial therapy to reduce mortality, leaving an everincreasing population of ACS survivors in need of long-term outpatient care. Depending upon their specific ACS manifestation, survivors are at variable  but elevated risk for a host of adverse cardiac events as consequences of the ACS episode itself, and at increased risk for recurrent coronary episodes. Post-ACS management therefore has 2 general goals: limitation of late complications (total cardiovas cardio vascul cular ar mort mortali ality, ty, sud sudden den car cardia diacc dea death, th, arrhyt arrhythmi hmias, as, str stroke oke,, lat latee heart heart failure) and reduction in recurrent clinical coronary events. This latter group can be further divided into reducing atherosclerotic burden or stabilizing existing plaques, and lowering the probability of coronary thrombus formation (and subsequent ischemia or infarction) should plaque rupture occur. Many interventions have been identified by randomized trials to reduce risk, while others that have less robust supporting evidence are generally considered advisable by experts in the field. Recommendations in this article are based upon evidence-based guidelines and

 

expe ex pert rt op opin inio ion n pa pane nels ls (se (seee Re Refer feren ence ces), s), an and d tr tria ials ls th that at have have mo modi difi fied ed th thes esee recommendations after publication. Key Questions

In deciding on the optimal post-ACS regimen for any individual patient, several key pieces of data are needed.

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First First,, did did the the pa pati tien entt un unde derg rgo o co coron ronary ary int interv erven enti tion on in incl clud udin ing g co coro rona nary ry stenting, and if so, was this a drug-eluting or bare metal stent?

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Was the there re evid evidenc ence, e, eith either er by angi angiog ograp raphy hy or noni noninva nvasiv sivee coron coronary ary tes testin ting, g, that the patient has residual ischemia?

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What are tthe he pa patient tient’s ’s new basel baseline ine lleft eft v ventric entricular ular eejecti jection on fra fractio ction n (LV (LVEF), EF),  blood pressure, and fasting lipid profile?

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Doe Doess the pat patien ientt refra refrain in fro from m toba tobacco cco us use, e, exe exerci rcise se reg regula ularly rly,, and adhere adhere to an anti-atherogenic diet?

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Is the the pa pati tien entt d dia iabe beti tic? c?

It may be necessary for the office practitioner to obtain updated information to answer these questions. Particularly following large infarcts, plasma lipids may demonstrat demon stratee lowe lowerr low-d low-densit ensity y lipop lipoprotei rotein n (LDL) and highe higherr trigly triglyceride ceride (TG) levels lev els dur during ing the ind index ex hos hospit pitali alizat zation ion,, as a non nonspe specif cific ic respon response se to sys system temic ic

 

inflammation. These values typically return to baseline about 6 weeks after an ACS.. Hig ACS High-d h-dens ensity ity lip lipopr oprote oteins ins (HD (HDL) L) are som somewh ewhat at les lesss sen sensit sitive ive to acu acute te nons no nspe peci cific fic ch chan ange ges. s. Du Duee to reve revers rsib ible le my myoc ocar ardi dial al dy dysfu sfunc ncti tion on (stu (stunn nnin ing), g), measured LVEF early after ACS may be lower than the patient’s new baseline, and repeat assessment at 6 to 8 weeks is a more reliable indicator of residual systolic function.1 Patients treated acutely without coronary angiography or intervention function.1 may have had only low-level exercise testing before discharge; in these cases, maximal stress testing, usually with noninvasive imaging (echo or myocardial scintigraphy) and using pharmacologic stress in patients unable to exercise to maximal heart rate for any reason, should be performed at about 6 weeks from discharge.1 discharge.1 Medication Therapy

Several drug classes have been shown to reduce one or more post-ACS adverse cardiac events, whether mortality, reinfarction, need for revascularization, hospital readmission, stroke, cardiac arrest, or late heart failure. Note that listed doses are study-derived targets; initial doses and titration schedules will depend upon clinical variables (heart rate, blood pressure, heart failure f ailure severity). Beta-blockers are a mainstay of postinfarction therapy, reducing mortality (particularly sudden death), recurrent coronary events, angina, and blood pressure. Sele Se lect ctio ion n of indi indivi vidu dual al drug drugss wi with thin in the the cl clas asss is ba base sed d up upon on th thee pres presen ence ce or  abse ab senc ncee of LV dy dysfu sfunc ncti tion on.. Ea Early rly po post st-M -MII st stud udie iess ex excl clud uded ed pa pati tien ents ts wi with th significant heart failure and demonstrated that timolol (10 mg twice a day [BID]),  propranolol (80-120 mg three times a day [TID]), and metoprolol (100 mg BID) reduced post-MI events. More recently, carvedilol (25 mg BID) was shown to have a similar benefit in patients with heart failure and reduced LVEF early after an MI,

 

as was time-release metoprolol (200 mg daily) when started several months later in such patients with moderate heart failure. At target doses, little difference in beta-2 effects is seen among these drugs. Although likely that other beta blockers afford such protection, and a possibility exists for no measurable benefit in patients with small troponin elevations, normal LV function, and complete revascularization, an evidence-b evid ence-based ased appro approach ach sugg suggests ests presc prescriptio ription n of carved carvedilol ilol for early post-MI   patients with LV dysfunction and either metoprolol, timolol, or propranolol for  those tho se wit with h no normal rmal LV fun functi ction. on. Con Contrai traindi ndicat cation ionss inc includ ludee mod modera eratete-sev severe ere reactive airway disease, symptomatic bradycardia, heart block greater than first degree (without implanted pacemaker present), and hypotension. Angiotensin-converting enzyme inhibitors (ACEi) reduce mortality and late heart failure when started orally early (first 24 hours after ACS presentation) in nonhypotensive patients without other contraindications (severe renal impairment, hyperkalemia, known adverse reaction to ACEi in past). The protective effects of  several ACEi (captopril 50 mg TID, enalapril 10 mg BID, ramipril 5 mg BID, trandolapril 4 mg daily) in patients with significant systolic heart failure following acute MI have been well documented, as have those of enalapril (10 mg BID) in  patients with a mildly depressed LVEF but no clinical heart failure. Additionally, several studies of the ability of ACEi to reduce cardiac events in patients without LV dysfunction included large subgroups (50%-65%) of patients who had suffered   previous previous ACS. In these cohorts, high-risk patients showed improved outc outcomes omes with ramipril 10 mg daily, and low-to-moderate risk patients with perindopril 8 mg daily. dai ly. Ben Benefi efits ts wer weree refl reflect ected ed in com compos posite ite end endpoi points nts of card cardiov iovasc ascula ularr dea death, th, resuscitated cardiac arrest, or stroke, depending upon the specific study and risk   population examined.

 

Angiotensin receptor blockers (ARB) are recommended in ACEi-intolerant  patients with LVEF <40% and clinical evidence of heart failure. Valsartan 160 mg BID BI D an and d ca cand ndes esar arta tan n 32 mg ha have ve be been en st stud udie ied d wi with th ou outc tcom omes es ge gene nera rall lly y comparable with ACEi. One trial suggested an additional benefit of adding an ARB (candesartan) to an ACEi in this population, but this single study requires further validation before combined therapy can be considered a standard of care. It should be noted that, in limited studies thus far, patients with LVEF >40% showed no demonstrable benefit from ARB therapy. Contraindications to ARBs are similar  to those of ACEi, although some frequent side effects (eg, cough) are decidedly less frequent with ARBs. Aldosterone receptor antagonists (ARA) have been studied in 2 distinct   pop popul ulat atio ions ns:: pa pati tien ents ts wi with th dist distan antt MI an and d mo mode dera rate te to seve severe re he hear artt fa fail ilur uree (spironolactone 25 mg daily); and patients with recent ACS, LVEF <40%, and clinical signs of heart failure (eplerenone 25-50 mg daily). In both trials, combined endpoi end points nts (in (inclu cludin ding g all all-ca -cause use mort mortali ality ty and re-h re-hosp ospita italiz lizati ation) on) wer weree red reduce uced. d. Contraindications include baseline hyperkalemia (K >5 mEq/L) and significant azotemia azote mia (creatini (creatinine ne >2.5 mg/dL mg/dL). ). ARAs have been added to ACEi in both trials trials,, and to AC ACEi Ei or ARB plu pluss bet beta-b a-bloc locker kerss wit with h epl eplere erenon none. e. Cau Cautio tion n sho should uld be exer ex erci cise sed d whe hen n pres rescri cribin bing ARAs ARAs to an any y pa pati tien entt at in incr creease ased ri rissk for  for  hyperkalemia. Lipid-lower Lipid -lowering ing therap therapy y with HMG-C HMG-Co-A o-A reduc reductase tase inhib inhibitors itors (“stat (“statins”) ins”) re redu duce cess virt virtua uall lly y al alll ca card rdia iacc ev even ents ts in the the po post st-A -ACS CS pa pati tien entt as pa part rt of a comprehensive secondary prevention program. Recommended lipid goals in this  population include LDL <70 mg/dL, HDL >40 mg/dL, and TG >150 mg/dL, with the primary focus on LDL levels, based on 2 large studies of low-versus-high intensity statin therapy. Earlier trials showed secondary prevention benefit from

 

lesss agg les aggress ressive ive lip lipid id low loweri ering ng (pr (prava avasta statin tin 40 mg, sim simvas vastat tatin in 40 mg). Wh While ile intensive LDL lowering arms have typically included atorvastatin 80 mg once daily, it remains unclear whether achieving similar LDL levels with other statins (whe (w here re po poss ssib ible le)) wo woul uld d af affo ford rd the the sa same me be bene nefit fit.. Wh Whil ilee cl clin inic ical al tri trial alss ha have ve demonstrated benefit from raising HDL with fibrates (gemfibrizol 600 mg BID) in   patie patients nts not rec receiv eiving ing sta statin tin the therap rapy, y, HD HDL-t L-targ argete eted d the therap rapy y has not yet been been combined with high-dose statins to determine if benefits are additive and outweigh risks from adverse drug interactions. interactions.1 1 Fenofibrate appears to cause less myositis than tha n gem gemfib fibriz rizol ol whe when n com combin bined ed wit with h hig high-d h-dose ose sta statin tins, s, but pos positi itive ve out outcom comee studies are lacking with this agent. Niacin (crystalline niacin 500-750 mg BID or  equivalent) is also effective at raising HDL and reducing TG levels, but careful monitoring of hepatic transaminases should be performed when prescribed with statin sta tins. s. Whethe Whetherr oth other er LDL LDL-lo -lower wering ing age agents nts (ez (ezeti etimib mibe, e, bin bindin ding g res resins ins)) hav havee similar outcome benefits to those of statins, or additional benefits when added to stat statin ins, s, re rema main inss unc ncle lear ar.. Fi Fish sh oil (900 (900 mg da daiily of com ombi bin ned ome meg ga-3 a-3  polyunsaturated fatty acids) appears to reduce combined atherosclerotic endpoints in post-ACS patients when added to other standard therapies. This is very well tolerated, and the benefit does not appear to track with a specific lipoprotein change. Antiplatelet therapy is a mainstay in reducing recurrent coronary events in  post-ACS patients. Aspirin, 81-162 mg once daily, should be prescribed for life in all patients not strictly intolerant of the drug. Clopidogrel (75 mg daily) has clear  indications now for all ACS manifestations, including those receiving medical management manag ement,, throm thrombolyt bolytic ic therap therapy, y, or primary coronary stenting stenting.. The optim optimal al duration of clopidogrel therapy remains unclear and is in part driven by the initial therapy received by the patient. At a minimum, non-ST elevation ACS survivors

 

treated treat ed medically should receiv receivee clopi clopidogre dogrell for 3 month monthss (up to 1 year), patie patients nts receiving bare metal stents for 4 weeks, and those with drug-eluting stents for 3-6 months (depending upon brand and eluted drug). The duration of clopidogrel therapy remains a disputed topic at the time of this writing, and readers are enco en coura urage ged d to se seek ek info informa rmati tion on from from regu regula larl rly y up upda date ted d sourc sources es for for furt furthe her  r  guidance. guid ance. Othe Otherr antip antiplatel latelet et medic medication ationss (dipy (dipyridimo ridimole, le, oral glyco glycoprote protein in IIb/II IIb/IIIa Ia inhibitors) have no role in post-ACS management. Although protracted outpatient therapy with low molecular weight heparins are of no ben benefi efitt to the these se pat patien ients, ts, ora orall war warfari farin n doe doess affo afford rd som somee pro protec tectio tion n against recurrent coronary events and is indicated primarily for patients with atrial fibril fib rillat lation ion,, lef leftt ven ventri tricul cular ar ane aneury urysms sms,, and lar large ge ant anterio eriorr ST ele elevat vation ion MIs to reduce the risk of stroke and peripheral embolization. Warfarin carries a higher   bleeding risk than either aspirin or clopidogrel and, when added to aspirin, does not reduce coronary events more than aspirin alone. Long-acting nitrates should be prescribed only as part of a combination regimen in selected patients with heart failure (see below) or for patients with symptomatic exertional angina. They are poor antihypertensives and, when used alone, have failed to demonstrate reduction in any major clinical outcomes. When  prescribed, care should be taken to provide a 10- to 12-hour nitrate-free interval to avoid tachyphylaxis. Transdermal nitroglycerin patches (12 hours daily) or oral isosorbide mononitrate (dosed once each morning) are the simplest ways to avoid nitrate tolerance. Use of calci calcium um channel blockin blocking g drugs (CCB) should in gene general ral be limit limited ed to patients without heart failure or LV dysfunction who are intolerant of beta   block blockers ers (verap (verapami amil), l), or hav havee res residu idual al hyp hypert ertens ension ion or ang angina ina des despit pitee oth other  er 

 

therapies (amlodipine). Studies of CCBs have been variable, with many of those showing benefit only in patients not receiving beta-blockers. Although a combination of ACEi/ARB, beta-blockers, and ARA may be sufficient to control hypertension, the blood pressure goal in post-ACS patients is <130/85 mm Hg or <130/80 mm Hg in patients with diabetes or chronic kidney disease. In the presence of residual symptomatic heart failure, loop diuretics are typica typ ically lly ind indica icated ted to con contro troll exc excess ess volum volumee and hel help p low lower er bl blood ood pre pressu ssure. re. Hydralazine 75 mg plus isosorbide dinitrate 40 mg, both three times a day, would constitute third- or fourth-line therapy in African Americans with heart failure, or  whose blood pressure remains above goal despite ACEi/ARB and beta-blocker  therapy at target or maximum-tolerated doses. In the absence of other compelling indications, the patient without heart failure should receive additional treatment with wit h a thi thiazi azidede-typ typee diu diureti retic, c, the then n fou fourth rth-- or fif fifthth-lin linee antihy antihyper perten tensiv sivee age agents nts (sympatholytics, calcium channel blockers) based upon expected side effects in the individual patient already receiving evidence-based therapy. Therapeutic lifestyle modifications (see below) are part of every antihypertensive regimen. Therapeutic Lifestyle Changes

Regular aerobic exercise, including formal cardiac rehabilitation programs, should be part of every patient’s long-term management. Besides reducing blood  pressure, helping to control obesity and its complications, and raising HDL levels, a minimum of 120 minutes of moderate aerobic activity weekly in 3-4 sessions (ideally, 20-30 min daily) improves the patient’s sense of well-being and hastens return to normal activit activities. ies. Abstinen Abstinence ce from tobacco is essen essential, tial, and every effort and tool available should be employed to help patients stop smoking. Diets low in sodium, saturated fat, and cholesterol (replaced by mono- and poly-unsaturated

 

fats), fat s), hig high h in die dietar tary y fib fiber er and com comple plex x car carboh bohydr ydrate ates, s, and dev devoid oid of exc excess ess calories remain most commonly recommended in patients with atherosclerosis. More specific diets (eg, Mediterranean) have shown mixed results when actual food was not provided free to patients. “Trendy” diets, particularly those high in fat and an d low low in carb carbo ohy hyd drat rates es,, hav avee show shown n no lon ong g-t -teerm ben eneefi fitt in ei eitther  her  cardiovascular disease or weight reduction. Limited alcohol intake (1-2 servings daily) raises HDL levels; however, excessive intake can elevate blood pressure and  produce other complications and should be discouraged. Although a detailed review of diabetes management is beyond the scope of  thiss dis thi discus cussio sion, n, com compre prehen hensiv sivee ris risk k fac factor tor mod modifi ificat cation ion inc includ ludes es agg aggres ressiv sivee glycem gly cemic ic con contro trol, l, wit with h goa goall hem hemogl oglobi obin n A1C lev levels els bel below ow 7.0 mg/ mg/dL dL usi using ng combined drug, diet, and exercise therapy. Treatment of the metabolic syndrome (centr (ce ntral al obe obesit sity, y, glu glucos cosee int intole oleran rance/ ce/dia diabet betes, es, hig high h nor normal mal or ele elevat vated ed blo blood od  pressure, elevated TG, low HDL) centers around weight, blood pressure, and lipid management. Cardiology Referral for Additional Interventions

Two groups of post-ACS patients routinely require subspecialty referral: those with demonstrable residual ischemia and those with moderate-severe heart failure (LVEF <35% and functional class III or IV symptoms) more than 1 month following their coronary event. Depe De pend ndin ing g up upon on spec specif ific ic co comb mbin inat atio ions ns of co coro rona nary ry le lesi sion onss an and d le left ft ventricular function, revascularization (whether by percutaneous intervention or   bypass graft surgery) will improve long-term survival in many patients after ACS. Beca Be caus usee the the de deci cisi sion on as to the the de degr gree ee of rev revas ascu cula lari riza zati tion on po poss ssib ible le an and d th thee

 

risk:benefit ratio of the available approaches depends on technical issues beyond th thee sc scop opee of the the prim primar ary y care care inte intern rnis ist, t, co cons nsul ulta tati tive ve op opin inio ion n from from a ge gene nera rall cardiologist, interventional cardiologist, or cardiac surgeon is necessary in any  patient demonstrating post-event myocardial ischemia. Patients more than 1 month out from their MI who have an LVEF <30%35% will enjoy a significant mortality reduction with placement of an internal cardiac defibrillator (ICD). Similarly, patients with clinical heart failure (functional class III or IV) and a wide (>120 ms) QRS can expect both symptomatic and surviv sur vival al ben benefi efitt fol follow lowing ing imp implan lantat tation ion of a biv bivent entricu ricular lar pac pacema emaker ker (ca (cardi rdiac ac resynchronization therapy, or CRT). Some patients will need devices with both capabilities. Therefore, patients who meet the clinical and noninvasive criteria for  consideration for ICD or CRT should be referred to a cardiac electrophysiologist for further evaluation and therapy. Conclusion

Majo Ma jorr ad adve verse rse ca card rdia iacc ev even ents ts can can be si sign gnifi ifica cant ntly ly redu reduce ced d in pa pati tien ents ts following follo wing an acute coron coronary ary syndro syndrome. me. Beta Beta-block -blockers, ers, angio angiotensi tensin n anta antagonis gonists, ts, statins and other lipid-lowering treatments, and antiplatelet therapy combine with therapeutic lifestyle changes and atherosclerosis risk factor modification to help  patients live longer, with fewer symptoms and better quality of life. Aldosterone inhibitors, inhib itors, hydra hydralazin lazine/ni e/nitrate trates, s, warfa warfarin, rin, and perha perhaps ps calci calcium um chann channel el bloc blockers kers add benefit in select subpopulations, as can revascularization and ICD/CRT. The   prim primar ary y care care prov provid ider er shou should ld st stri rive ve to reac reach h rec recom ommen mende ded d go goal alss for for bl bloo ood d   press pressure ure,, lip lipid id lev levels els,, beh behavi avior, or, and med medica icatio tion n dos doses es to max maximi imize ze ben benefi efitt in  patients following ACS.