Secondary Prevention Following MI

The long-term goals following MI are to: (a) control modifiable CHD risk-factors; (b) prevent the development of heart failure; (c) prevent recurrent MI and stroke; and (d) prevent death, including sudden cardiac death. Pharmacotherapy, which has been proven to decrease mortality, heart failure, reinfarction, or stroke, should be initiated prior to hospital discharge for secondary prevention. Guidelines from the ACQ AHA suggest that in the absence of contraindications, following MI from either STE ACS or NSTEACS, patients should receive indefinite treatment with ASA, a ft-blocker, and an ACE inhibitor.2'3'47 For NSTE ACS, clopidogrel should be added to ASA for at least 1 month and ideally for up to 12 months and for STE ACS for at least 2 weeks (unless they undergo PCI where the duration of clopidogrel therapy depends on stent type), and up to 1 year.3 Most patients will receive a statin to reduce low-density lipoprotein cholesterol to less than 100 mg/dL (2.59 mmol/L), and ideally less than 70 mg/ dL (1.81 mmol/L). Newer therapies include eplerenone, an aldosterone antagonist. For all ACS patients, treatment and control of modifiable risk factors such as HTN, dyslipidemia, and diabetes mellitus (DM) is essential. Benefits and adverse effects of long-term treatment with these medications are discussed in more detail below.

© Because the costs for chronic preventative pharmacotherapy are the same for primary and secondary prevention, while the risk of events is higher with secondary prevention, secondary prevention is more cost effective than primary prevention of CHD. Pharmacotherapy demonstrating cost effectiveness to prevent death in the ACS and post-MI patient includes fibrinolytics ($2,000 to $33,000 cost per year of life saved), ASA, glycoprotein IIb/IIIa receptor inhibitors ($13,700 to $16,500 per year of life added), P-blockers (less than $5,000 to $15,000 cost per year of life saved), ACE inhibitors ($3.000 to $5.000 cost per year of life saved), eplerenone ($15,300 to $32,400 per year of life gained), statins ($4,500 to $9,500 per year of life saved) and gemfibrozil ($17,000 per year of life saved).46-55 Because cost-effectiveness ratios of less than $50,000 per added life-year are considered economically attractive from a societal perspective, pharmacotherapy described above for ACS and secondary prevention are standards of care because of their efficacy and cost attractiveness to payors.

Aspirin

ASA decreases the risk of death, recurrent infarction, and stroke following MI. ASA prescription at hospital discharge is a quality care performance measure in MI pa-tients.9,14 All patients should receive ASA indefinitely; those patients with a contrain-

dication to ASA should receive clopidogrel. ' The risk of major bleeding from chronic ASA therapy is approximately 2% and is dose-related. ASA doses higher than 75 to 81 mg are no less effective than doses of 160 to 325 mg, but do have lower rates of bleeding. Therefore, chronic doses of ASA should not exceed 81 mg.46 For patients receiving intracoronary stents, the dose of ASA recommended by the ACC/AHA PCI guidelines in combination with clopidogrel is 162-325 mg for the duration specified by type of stent followed by low-dose ASA (see Table 8-2) but this is based upon consensus recommendations and not on randomized trials of ASA dosing.4 In contrast, the American College of Chest Physician guidelines recommend low-dose ASA in combination with clopidogrel for all patients, including those with stents.19,29,47

Clopidogrel

For patients with either STE or NSTE ACS, clopidogrel decreases the risk of cardi-17,18,26

ovascular events. ' ' The ACC/AHA guidelines suggest a minimum therapy duration of 1 month in patients following NSTE ACS who are managed conservatively, and ideally up to 12 months. In patients receiving clopidogrel for STE MI who do not undergo PCI, clopidogrel should be administered for at least 14 to 28 days.26 Patients who have undergone a PCI with a bare metal stent should receive clopidogrel for at least 1 month, ideally up to 1 year, and for patients receiving a drug-eluting stent for at least 12 months.4

P-Blockers, Nitrates, and Calcium Channel Blockers

Current treatment guidelines recommend that following an ACS, patients should re-

ceive a P-blocker indefinitely. ' whether they have residual symptoms of angina or not.59 Overwhelming data support the use of P-blockers in patients with a previous MI. Currently, there are no data to support the superiority of one P-blocker over another.

Although P-blockers should be avoided in patients with decompensated heart failure from left ventricular systolic dysfunction complicating an MI, clinical trial data suggest that it is safe to initiate P-blockers prior to hospital discharge in these patients once heart failure symptoms have resolved.49 These patients may actually benefit more than those without left ventricular dysfunction. 0 In patients who cannot tolerate or have a contraindication to a P-blocker, a calcium channel blocker can be used to prevent anginal symptoms, but should not be used routinely in the absence of 23,51

such symptoms. '

Finally, all patients should be prescribed short-acting, SL NTG or lingual NTG

spray to relieve any anginal symptoms when necessary and instructed on its use. Chronic long-acting nitrate therapy has not been shown to reduce CHD events following MI. Therefore, IV NTG is not routinely followed by chronic, long-acting oral nitrate therapy in ACS patients who have undergone revascularization, unless the patient has chronic stable angina or significant coronary stenoses that were not revascu-larized.51

ACE Inhibitors and ARBs

ACE inhibitors should be initiated in all patients following MI to reduce mortality, decrease reinfarction, and prevent the development of heart failure.2,3,9 Dosing and contraindications are described in Table 8-2. The benefit of ACE inhibitors in patients with MI most likely comes from their ability to prevent cardiac remodeling. The largest reduction in mortality is observed in patients with left ventricular dysfunction (low LVEF) or heart failure symptoms. Early initiation (within 24 hours) of an oral ACE inhibitor appears to be crucial during an acute MI, as 40% of the 30-day survival benefit is observed during the first day, 45% from days 2 to 7, and approximately

15% from days 8 to 30. However, current data do not support the early administration of IV ACE inhibitors in patients experiencing an MI, as mortality may be increased.53 Administration of ACE inhibitors should be continued indefinitely. Hypotension should be avoided, as coronary artery filling may be compromised. Additional trials suggest that most patients with CAD, not just ACS or heart failure patients, benefit from ACE inhibitors. Therefore, ACE inhibitors should be considered in all patients following an ACS in the absence of a contraindication.

Many patients cannot tolerate chronic ACE inhibitor therapy secondary to adverse effects outlined below. The ARBs, candesartan and valsartan, have been documented in trials to improve clinical outcomes in patients with heart failure.54,55 Therefore, either an ACE inhibitor or candesartan or valsartan are acceptable choices for chronic therapy for patients who have a low LVEF and heart failure following MI. Since more than five different ACE inhibitors have proven benefits in MI while only two ARBs have been studied, the benefits of ACE inhibitors are generally considered a class effect while the benefits of ARBs are still under study. More recently, telmisartan has been shown to be equivalent to ramipril for prevention of CVD events or hospitaliz-ation for heart failure in patients with CAD or at high risk of CVD events.56 Nevertheless, a subsequent trial in ACE inhibitor intolerant patients produced more modest

results. ACE inhibitor prescription (or alternatively an ARB) at hospital discharge following MI, in the absence of contraindications, to patients with depressed LVF (EF less than 40%) is currently a quality performance measure for MI.3,14

Besides hypotension, the most frequent adverse reaction to an ACE inhibitor is cough, which may occur in up to 30% of patients. Patients with an ACE inhibitor cough and either clinical signs of heart failure or LVEF less than 40% may be prescribed an ARB.3 Other, less common but more serious adverse effects to ACE inhibitors and ARBs include acute renal failure, hyperkalemia, and angioedema.

Aldosterone Antagonists

To reduce mortality, administration of an aldosterone antagonist, either eplerenone or spironolactone, should be considered within the first 2 weeks following MI in all patients who are already receiving an ACE inhibitor (or ARB) and have an LVEF of equal to or less than 40% and either heart failure symptoms or diagnosis of DM.3 Al-dosterone plays an important role in heart failure and in MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, HTN, left ventricular hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. Aldoster-one antagonists have been shown in experimental and human studies to attenuate these adverse effects.58 Spironolactone decreases all-cause mortality in patients with stable, severe heart failure.59

Eplerenone, like spironolactone, is an aldosterone antagonist that blocks the min-eralocorticoid receptor. In contrast to spironolactone, eplerenone has no effect on the progesterone or androgen receptor, thereby minimizing the risk of gyne-comastia, sexual dysfunction, and menstrual irregularities. In a large clinical trial,60 eplerenone significantly reduced mortality, as well as hospitalization for heart failure in post-MI patients with an EF less than 40% and symptoms of heart failure at any time during hospitalization. The risk of hyperkalemia, however, was increased. Therefore, patients with a SCr greater than 2.5 mg/dL (221 ^mol/L) or CrCl less than 50 mL/min or serum potassium concentration of greater than 5.0 mmol/L (5.0 mEq/L) should not receive eplerenone (in addition to either an ACE inhibitor or ARB). Currently, there are no data to support that the more selective, more expensive eplerenone is superior to, or should be preferred to, the less expensive generic spironolactone unless a patient has experienced gynecomastia, breast pain, or impotence while receiving spiro-nolactone. Finally, it should be noted that hyperkalemia is just as likely to appear with both of these agents, and is more common in patients receiving concomitant ACE inhibitors.

Lipid-Lowering Agents

There are now overwhelming data supporting the benefits of statins in patients with CAD in prevention of total mortality, cardiovascular mortality, and stroke. According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel recommendations, all patients with CAD should receive dietary counseling and pharma-cologic therapy in order to reach a low-density lipoprotein (LDL) cholesterol of less than 100 mg/dL (2.59 mmol/L), with statins being the preferred agents to lower LDL cholesterol. 1 Results from landmark clinical trials have unequivocally demonstrated the value of statins in secondary prevention following MI in patients with moderate to high cholesterol.62,63 Although the primary effect of statins is to decrease LDL cholesterol, statins are believed to produce many non-lipid-lowering or "pleiotropic" effects such as anti-inflammatory and antithrombotic properties. Newer recommendations from the NCEP give an optional LDL cholesterol goal of less than 70 mg/dL (1.81 mmol/L).63,64 In patients with an ACS, statin therapy initiation should not be delayed and statins should be prescribed at or prior to discharge in most patients.65 Statin prescription at hospital discharge is currently a quality performance measure for MI.14

A fibrate derivative or niacin should be considered in select patients with a low high-density lipoprotein (HDL) cholesterol less than 40 mg/dL (1.04 mmol/L) and/or a high triglyceride level greater than 200 mg/dL (2.26 mmol/L). In a large randomized trial of men with established CAD and low levels of HDL cholesterol, the use of gemfibrozil (600 mg twice daily) significantly decreased the risk of nonfatal MI or death from coronary causes.66 Studies with fenofibrate have produced less definitive results.

Other Modifiable Risk Factors

Smoking cessation, managing HTN, weight loss, and tight glucose control for patients with DM, in addition to treatment of dyslipidemia, are important treatments for sec ondary prevention of CHD events. Smoking cessation counseling at the time of discharge following MI is a quality care performance measure. The use of nicotine patches or gum, or of bupropion alone or in combination with nicotine patches, should be considered in appropriate patients. HTN should be strictly controlled according to published guidelines.67 Patients who are overweight should be educated on the importance of regular exercise, healthy eating habits, and reaching and maintaining an ideal weight.6 Finally, because diabetics have up to a four-fold increased risk of mortality compared to nondiabetics, the importance of tight glucose control, as well as other CHD risk factor modifications, cannot be overstated.69

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