Secondary Prevention of Coronary Artery Disease

# I.  Blood Pressure Control

## Background
- JNC 7 set new definitions for blood pressure goals based upon reliable readings on at least two separate occasions.
- Normal blood pressure: SBP<120 mmHg and DBP<80 mmHg
- Prehypertension: SBP 120-139 mmHg or DBP 80-89 mmHg
- Hypertension: SBP 140 mmHg or DBP90 mmHg
- The risk of cardiovascular disease begins at 115/75 mmHg and doubles with each increment of 20/10 mmHg.

## Goals of Treatment
- Blood pressure <130/80, especially if patient also has diabetes mellitus or chronic kidney disease.
- Increase event-free survival, and decrease death rates.
- Regression of left ventricular hypertrophy, a surrogate risk marker for myocardial infarction, congestive heart failure, and sudden death.

## Treatment Choices
- Aldosterone Antagonists
- Angiotensin Converting Enzyme Inhibitors (ACE-I)
- Angiotensin Receptor Blockers (ARB)
- Beta Blockers
- Calcium Channel Blockers
- Diuretics

## Aldactone Antagonists

### Spironolactone
- Acts as a potassium sparing diuretic via selective blockade of aldosterone.
- Dose for hypertension 25-50 mg/day.
- Dose for Class III-IV congestive heart failure 21.5-25mg/day.
- Requires close monitoring of potassium and creatinine.  Discontinue use if Cr>4 mg/dL or K>5 mEq/L.

### Eplerenone
- Selective aldosterone blocker.
- Dose for hypertension 50mg/day, may increase to 50mg BID.
- Dose for CHF post-MI 25mg/day, titrate to 50mg/day within 4 weeks; as tolerated.
- Use with caution with CYP3A4 inhibitors.  Requires close monitoring of creatinine and potassium, cannot use if K>5.5 or CrCl2.0 mg/dL in males or >1.8 mg/dL in females; Clcr <50 mL/minute.

## Angiotensin Converting Enzyme Inhibitors
- Inhibit the conversion of angiotensin I to angiotensin II.

## Angiotensin Receptor Blockers
- Selective angiotensin I receptor blocker.
- Use if patients are intolerant of ACE-I.

## Beta Blockers
- Inhibit beta-1 adrenergic receptors in the myocardium decreasing myocardial contractility and heart rate, thereby reducing myocardial oxygen demand in increasing oxygen supply.
- Titrate to HR 50-60 bpm.

## Calcium Channel Blockers
- Inhibit myocardial and smooth muscle contractility improving blood flow to the myocardium and decreasing oxygen demand.

## Diuretics
- Loop or thiazide diuretics may be used as needed to treat HTN but have not been shown to have morbidity or mortality benefit in post-MI patients.

## Summary: Advantages of Each Choice
- B-blockers should be started within 24 hours of onset of acute coronary syndrome, and continued indefinitely in post-myocardial infarction patients unless contraindicated.  IV beta-blockers should be used with caution.  The COMMIT trial showed an increased risk of cardiogenic shock with IV beta-blockers in patients who presented with tachycardia, hypotension, or CHF.
- ACE-I should be started within 24 hours and continued indefinitely in all patients with CHF, LVEF <=40%, HTN, DM, or CKD unless contraindicated.  ACE inhibitors are associated with the common side effect of cough.  In patients who cannot tolerate ACE-Is data from the VALIANT and OPTIMAAL trials suggest that ARBs are as effective as ACE-Is for prevention of cardiovascular events following myocardial infarction.  There is no additional benefit to be gained from combination of ACE-I and ARB therapy.  In addition they should be used with caution in women of childbearing age as they are contraindicated during pregnancy due to teratogenic effects.
- The EPHESUS trial showed that eplerenone decreased morbidity and mortality in patients with MI, LV dysfunction, and CHF or diabetes and epidemiological trials suggest that eplerenone and aldactone are underutilized.

## Making a Selection
- All patients post-myocardial infarction should receive b-blockers and ACE inhibitor in the absence of contraindications.
- Patients with Diabetes Mellitus should be treated with an ACE inhibitor or if intolerant, an ARB as first line therapy.
- Patients with LVEF<=40% should be treated with an ACE inhibitor.
- Patients with angina may benefit from use of b-blocker, or if the ejection fraction is normal, a calcium channel blocker for patients with recurrent or persistent symptoms despite nitrates and b-blockers.

## Other Considerations
- Most patients with hypertension will require at least two antihypertensive agents to achieve their goal blood pressure.
- All patients should be counseled on lifestyle modification.

# II.  Antiplatelet Agents

## Background
- Rupture of a vulnerable atherosclerotic plaque leading to thrombus formation is the initiating event in most acute coronary syndromes.
- Reduction of platelet activation and aggregation to lessen the thrombus burden is the hallmark of targeted therapy for ACS.

## Goals of Treatment
- Increase event-free survival from non-fatal MI and CVA, and decrease cardiovascular death rates.

## Treatment Choices
- Aspirin
- Clopidogrel
- Prasugrel

## Aspirin
- Irreversibly inhibits cyclooxygenase 1, inhibiting thromboxane A synthesis and decreasing platelet aggregation.
- Aspirin reduces the risk of death or MI- RRR is 50% when compared to placebo for secondary prevention.
- 325mg/day x 1 month after ACS or PCI with stent placement, then can switch to 81mg/day indefinitely.

## Clopidogrel
- Blocks the P2Y12 adenosine diphosphate receptor on platelets decreasing activation and aggregation.
- 75mg/day immediately and for at least 12 months following ACS or PCI with stent placement.
- The addition of clopidogrel to aspirin following an acute coronary syndrome decreases future events as shown in several trials including CLARITY-TIMI 28, COMMIT/CCS2, CURE and CHARISMA.

## Prasugrel
- Irreversibly antagonizes the P2Y12 adenosine diphosphate receptor.
- TRITON-TIMI 38 was a trial of prasugrel versus clopidogrel in high-risk PCI patients that showed a statistically significantly decreased risk of the composite endpoint of death, myocardial infarction or stroke at 6-15 months in the prasugrel group.  The prasugrel group also had 50% less stent thrombosis and but a higher risk of TIMI major bleeding and fatal bleeding.
- Oral dose 60mg x 1 then 10mg/day (5mg/day in patients <60kg) in combination with aspirin.
- Black Box Warning- Contraindicated in pts with active bleeding or stroke/TIA history.  Not recommended in patients >75 years unless they are at high risk defined as diabetes mellitus or prior MI.

## Summary: Advantages of Each Choice
- Patients who have received a drug eluting stent should continue aspirin and clopidogrel for a minimum of 1 year.

## Anticipated Outcomes
- Prevent acute, early, and late in-stent thrombosis.

## Other Concerns
- The CAPRIE trial showed that clopidogrel is an acceptable alternative to aspirin in patients who are truly intolerant.

# III.  Anticoagulation

## Background
- Acute coronary syndromes are most often a thrombotic event.  Observational evidence that patients were more likely to develop a recurrent thrombotic complication soon after the discontinuation of IV heparin led to the hypothesis that anticoagulation with warfarin could further decrease the death rate following an acute event.
- It is known that it takes 3-6 months for a vulnerable plaque to heal, during which time the risk of re-thrombosis is high.  Early studies, prior to the current age of dual anti-platelet therapy, showed the addition of warfarin to aspirin could reduce ischemic events when compared to aspirin alone.

## Goals of Treatment
- Increase event-free survival, and decrease death rates.

## Treatment Choices
- Warfarin with goal INR 2-3

## Making a Selection
- Trials such as CURE that investigated dual antiplatelet strategy showed a similar magnitude of benefit from the addition of clopidogrel to aspirin that was seen with the additional of warfarin to aspirin, without the need for intensive monitoring of INR.
- Anticoagulation with warfarin is indicated in patients following myocardial infarction who have specific indications such as atrial fibrillation, left ventricular thrombus, mechanical prosthetic valve, or severe left ventricular dysfunction with apical/extensive wall motion abnormalities.
- In the absence of any of the above stated indications, the bleeding risk outweighs the potential benefit of oral anticoagulation.

## Anticipated Outcomes
- Prevention of stroke and systemic embolization of thrombus.

## Other Concerns
- Close monitoring of INR in patients on warfarin and dual antiplatelet therapy post-myocardial infarction is warranted to prevent excessive bleeding.

# IV.  Lipid Management

## Background
- The CARE trial established that lipid lowering through the administration of statin therapy can decrease cardiovascular event rates and mortality in patients with cardiovascular disease.
- PROVE-IT TIMI 22, TNT, IDEAL, A to Z and a meta-analysis of those trials showed an additional benefit to intensive lipid lowering therapy when compared to usual therapy.

## Goals of Treatment
- Goal LDL<70.
- Increase event-free survival (nonfatal MI, CVA and revascularization), and decrease all cause and cardiac death rates.
- Slow progression and induce regression of atherosclerosis.
- Anti-inflammatory properties.

## Treatment Choices
- Statins
- Ezetimibe
- Fibrates
- Niacin
- Bile Acid Binding Resins

## Statins
- Inhibit HMG Co-A Reductase, the rate limiting step in cholesterol biosynthesis.

## Ezetimibe
- Inhibits the absorption of cholesterol in the small intestine at the brush border.
- 10mg/day, avoid use in moderate to severe hepatic impairment

## Fibrates
- Inhibits triglyceride synthesis and increases catabolism of lipoproteins.

## Niacin
- Decreases the production of LDL and VLDL in the liver, increases lipolysis, decreases triglyceride esterification.
- 1.5-3g/day divided bid-tid (IR), 1-2g/day (ER)

## Bile Acid Binding Resins
- Binds intestinal bile acids and leads to excretion in feces rather than enteric reabsorbtion.

## Summary: Advantages of Each Choice
- Statin therapy is the only method shown to decrease mortality in patients with coronary artery disease and they remain first line therapy for the treatment of dyslipidemia and secondary prevention.  While it is likely that some of the benefit comes from lipid lowering and regression of atherosclerosis the benefit of statin use is seen earlier than plaque regression is apparent which leads to the conclusion that other pleiotrophic effects of statins such as antithrombotic or anti-inflammatory properties are also of importance.
- In patients who cannot tolerate a statin because of myopathy, it is recommended to try a less potent drug such as pravastatin or simvastatin at a low dose.
- Ezetimibe lowers LDL levels, but its long-term effects on hard outcomes as either monotherapy or in addition to a statin remain to be proven.
- Fibrates lower triglycerides and raise HDL levels.  They must be used with caution in patients on statins because of a significantly increased risk of muscle injury in patients on dual therapy.
- Niacin raises HDL levels but can also lead to hyperglycemia and hyperuricemia.  The side effects of facial flushing, pruritis and nausea are poorly tolerated by many though can be mitigated through the use of extended release preparations, and nighttime dosing.
- Bile acid sequestrants' can lower LDL from 10-24% depending on the dosages used.  Unfortunately their use is limited by gastrointestinal side effects, and it can also impair the absorption of medications such as warfarin and digoxin and should be used with care in patients on these medications.

## Anticipated Outcomes
- Goal LDL<70.

## Other Concerns
- The additional benefit of high-dose statin therapy comes at a risk of increased LFT abnormalities and myalgias.
- All patients should be counseled on lifestyle modification:

# V.  Immunizations

## Influenza Vaccine
- All patients should receive an annual influenza vaccine.
- The FLUVACS study is the only RCT to show a mortality benefit from flu vaccination.

## Goals
- Decrease cardiac events, rehospitalization, and death during flu season and beyond.

# VI.  Lifestyle Modification

## Weight Management
- Goal BMI 18.5-24.9
- Waist circumference men <40inches
- Waist circumference women <35inches
- Goal is 10%decrease in total body weight to manage CV risk factors, decrease cardiac and all cause mortality.
- Physical Activity: 30 minutes, 5-7 days/week.
- Nutrition Counseling
- Pain Management
- Depression Assessment

# VII.  Smoking Cessation

## Background
- Patients who smoke cigarettes have a higher all-cause and cardiovascular mortality when compared to patients who do not smoke.
- Current smoking is associated with a 50% increase in atherosclerosis progression over 3 years, as measured by carotid artery intimal-medial thickness, when compared to non-smoking patients.  Patients with environmental exposure to tobacco have a 20% increase in atherosclerosis progression compared to patients without environmental exposures.
- Patients with established coronary artery disease who continue to smoke despite a previous myocardial infarction or stable angina have a significantly increased risked of sudden cardiac death compared to those who quit smoking.
- Physician advice to quit smoking has been shown to increases abstinence rates.

## Goals of Treatment
- Decrease non-fatal myocardial infarction and all-cause mortality.
- Use the 5 A's:

## Treatment Choices
- Nicotine Replacement Therapy (NRT)
- Buproprion SR
- Varenicline

## Nicotine replacement therapy
- Nicotine receptor agonist.
- patch dosage: 21mg/24h for 4 weeks, 14mg/24h for 2 weeks, 7mg/24h for 2 weeks
- gum dosages: if smoking 1-24 cigarettes/day replace with 2mg gum, if 25+ 4mg gum up to 12 weeks
- lozenge if first cigarette less than 30 minutes from waking up 4mg/day, if first cigarette is after 30min 2mg/day for 12 weeks
- inhaler: 6-16 cartridges/day for up to 6 months
- nasal spray 8-40 doses/day for 3-6 months

## Buproprion SR
- Functions as a weak inhibitor of norepinephrine and dopamine reuptake.  Also thought to be dopaminergic and/or noradrenergic.
- 150mg qam x 3 days then 150mg bid, start 1-2 weeks prior to quitting.  Duration 7-12 weeks, up to 6 months
- Contraindications/Cautions- History of seizure or eating disorder.  Use of MAO inhibitors in the past 14 days.

## Varenicline
- Partial neuronal 4 2 nicotinic receptor agonist.  Also binds to the serotonin 5HT3 receptor.
- 0.5mg daily for days 5-7 before quit date, 0.5mg bid for days 1-4 before quit date, 1mg bid starting on quit date.  Duration 3-6 months.
- Contraindications/Cautions- Monitor for changes in mood, behavior, psychiatric symptoms and suicidal ideation.

## Making a Selection
- Smokers of 10 or more cigarettes per day should be encouraged to use NRT or pharmacologic therapy to assist in smoking cessation.
- In randomized controlled trials all forms of nicotine replacement therapy are associated with a 50% increased rate of smoking cessation when compared to placebo.  Nasal and oral delivery methods provide quick bursts of nicotine and are useful for acute cravings.  The patch provides more durable and consistent dosing.  The combined use of one or more forms of nicotine replacement therapy is beneficial to prevent withdrawal and treat cravings.
- Consider buproprion in patients with depressed mood and tobacco abuse.  Avoid in patients with bipolar disorder as it may unmask manic behavior.  Buproprion is good for patients who are concerned about weight gain as it has been shown in a randomized clinical trial to be associated with statistically less weight gain at 2 years when compared to placebo.  Because it takes a week for buproprion to reach a steady state its use must be planned ahead.
- Varenicline has been shown in some studies to be superior to buproprion and nicotine replacement therapies though the data is somewhat inconclusive.  The patients in all of the clinical trials showing a benefit to varenicline recieved extensive smoking cessation counseling at weekly visits which is not consistent with real world clinical practice.  There is a black box warning on this medication that there is increased risk of suicidal thoughts and aggressive and erratic behavior in patients treated with varenicline.  Patients on this medication should be observed for the development of neuropsychiatric symptoms.

## Anticipated Outcomes
- Complete tobacco cessation.

## Other Concerns
- Nicotine replacment therapy is well tolerated in patients with stable cardiovascular disease.
- While there is little data testing the safety of nicotine replacement therapy in patients with acute coronary syndromes it appears to be safe.  Nicotine delivered via replacement therapy has no effect on platelet activation, and minimal effect on heart rate and blood pressure.
- Combination therapy with NRT and buproprion may can be considered in patients who failed previous attempts using one therapy.  There is insufficient data to assess the safety and efficacy of varenicline combination therapy.