FIGURE 7-4. General treatment strategies for angina follow in clockwise fashion from the top center. (ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.)
Therapies to alleviate and prevent angina are aimed at improving the balance between myocardial oxygen demand and supply. Since angina usually results from increased myocardial oxygen demand in the face of a relatively fixed reduction in oxygen supply, drug treatment is primarily aimed at reducing oxygen demand. Short-acting nitrates are indicated to acutely relieve angina. P-Blockers, calcium channel blockers (CCBs), and long-acting nitrates are traditionally used to reduce the frequency of angina and improve exercise tolerance. In most patients with IHD, the most effective treatments to improve myocardial oxygen supply are invasive mechanical interventions, percutaneous coronary intervention (PCI), and coronary artery bypass graft (CABG) surgery, which are described later in the chapter in the section on interventional approaches.
Adverse treatment effects can largely be averted by avoiding drug interactions and the use of drugs that may have unfavorable effects on comorbid diseases. For example, P-blockers may exacerbate pre-existing bronchospasm. P-Blockers are not absolutely contraindicated in broncho-spastic disease, but should be avoided in patients with poorly controlled symptoms. While patients often require combination an-tianginal therapy, there is a potential pharmacodynamic drug interaction with the con-currentuse of P-blockers and nondihydropyridine CCBs. Since both drug classes slow electrical conduction through the atrioventricular (AV) node, serious bradycardia or heart block may result with their concomitant use. Appropriate drug dosing and monitoring also reduces the risk for adverse treatment effects. Drugs should be initiated in low doses, with careful up-titration as necessary to control symptoms of angina and cardiovascular risk factors.
Lifestyle modifications, including smoking cessation, avoidance of second-hand smoke, dietary modifications, increased physical activity, and weight loss, reduce cardiovascular risk factors, slow the progression of IHD, and decrease the risk for IHD-related complications. Cigarette smoking is the single most preventable cause of IHD and IHD-related death. Smoking may also attenuate the antianginal effects of drug therapy. The clinician should ascertain smoking status for the patient and family members on the patient s initial clinic visit. For patients and/or family members who smoke, clinicians should provide counseling on the importance of smoking cessation at each subsequent visit and referral to special smoking cessation programs. There are several pharmacologic aids for smoking cessation. Transdermal nicotine replacement therapy and bupropion have been studied in patients with IHD and appear safe.8,11
Weight loss, through caloric restriction and increased physical activity, should be encouraged in patients who have a body mass index greater than 25 kg/m . Dietary modification is important for risk factor management, and dietary counseling should be provided to all patients with newly diagnosed angina regardless of weight. The American Heart Association recommends a diet that includes a variety of fruits, vegetables, grains, low-fat or nonfat dairy products, fish, legumes, poultry, and lean 12
meats. Fatty fish, such as salmon and herring, are high in omega-3 fatty acids, which have been shown to reduce triglyceride concentrations and slow atherosclerotic 12
plaque progression. Specific dietary recommendations for patients with IHD should 2,12
include the following ' :
• Limit fat intake to less than 30% of total caloric consumption.
• Limit cholesterol intake to less than 200 mg/day.
• Consume at least two servings of fish per week. Alternatively patients may take omega-3 fatty acid supplements (1 g/day).
• Consume at least six servings of grains, five servings of fruits and vegetables, and two servings of nonfat or low-fat dairy products per day.
• Consider adding plant stanol/sterols (2 g/day) and/or viscous fiber (over 10 g/day) to lower LDL cholesterol. It is recommended that patients with diabetes consume 14 g of fiber for every 1,000 kcal consumed.
• Limit daily sodium intake to 2.4 g (6 g of salt) for blood pressure control.
Exercise facilitates both weight loss and blood pressure reduction. In addition, regular exercise improves functional capacity and symptoms in chronic stable angina.1 Recent guidelines recommend moderate intensity aerobic activity, such as brisk walking, ideally for 30 to 60 minutes every day. Medically supervised cardiac rehabilitation programs are recommended for high-risk patients.
FIGURE 7-5. The treatment algorithm for ischemic heart disease. It begins at the top (blue section), which suggests risk factor modifications as the first treatment modality. Moving down to the green section, appropriate antiplatelet therapy is selected. The purple section identifies patients at high risk for major adverse cardiac events and suggests appropriate drug therapy to decrease cardiovascular risk. The yellow section at the bottom recommends appropriate antianginal therapy. The minimum duration of clopidogrel therapy following intracoronary stent placement is as follows: at least 1 month for bare metal stents and at least 12 months for drug-eluting stents. (ACE-I, angiotensin-convert-ing enzyme inhibitor; ARB, angiotensin receptor blocker; BMS, bare metal stent; BP, blood pressure; CABG, coronary artery bypass graft; CCB, calcium channel blocker; DES, drug-eluting stent; IR, immediate-release; LA, long-acting; LDL, low-density lipoprotein; LV, left ventricular; NTG, ni-troglycerin; PCI, percutaneous coronary intervention; SL, sublingual.)
Interventional Approaches Percutaneous Coronary Intervention
When drug therapy fails or if extensive coronary atherosclerosis is present, PCI is often performed to restore coronary blood flow, relieve symptoms, and prevent major adverse cardiac events. Patients with one or more critical coronary stenoses (i.e., greater than 70% occlusion of the coronary lumen) detected during coronary angio-graphy may be candidates for PCI. Several catheter-based interventions may be used during PCI, including:
• Percutaneous transluminal coronary angioplasty (PTCA)
• Intracoronary bare metal stent placement
• Intracoronary drug-eluting stent placement
• Rotational atherectomy
During PCI, a catheter is advanced into the blocked coronary artery, as described for cardiac catheterization. If PTCA (i.e., balloon angioplasty) is performed, a balloon at the end of the catheter is inflated inside the artery at the site of the critical stenosis. When inflated, this balloon catheter displaces the atherosclerotic plaque out of the lumen of the artery, restoring normal myocardial blood flow. Most PCI procedures involve the placement of a small wire stent (similar in size and shape to the spring at the tip of a ball point pen) at the site of angioplasty. Coronary stenting involves use of a special balloon catheter containing the stent. When the balloon is inflated, the stent is deployed in the wall of the coronary artery, forming a sort of bridge or scaffold to maintain normal coronary blood flow. Either a bare metal stent or a drug-elut-ing stent may be used. Drug-eluting stents are impregnated with low concentrations of an antiproliferative drug (either paclitaxel or sirolimus), which is released locally over a period of weeks to inhibit restenosis or renarrowing of the coronary artery after PCI. A recent observational study demonstrated a significant reduction in all-cause mortality over a 4.5-year interval among patients who received a drug-eluting stent compared to those with a bare metal stent. 3 Stents themselves are thrombogenic, especially until they become endothelialized (covered in endothelial cells like a normal coronary artery). As such, dual antiplatelet therapy (discussed later) is required until the stent becomes endothelialized and perhaps indefinitely following stent placement to reduce the risk for stent thrombosis, MI, or death. Lastly, rotational atherectomy may be performed wherein a special catheter is used to essentially cut away the atherosclerotic plaque, restoring coronary blood flow.
As an alternative to PCI, CABG surgery, or open-heart surgery, may be performed if the patient is found to have extensive coronary atherosclerosis (generally greater than 70% occlusion of three or more coronary arteries) or is refractory to medical treatment. In the former case, CABG surgery has been shown to reduce mortality from IHD. During CABG surgery, veins from the leg (i.e., saphenous veins) or arteries from the arm (i.e., radial artery) or chest wall (i.e., internal mammary arteries) are surgically removed. In the case of venous or radial artery conduits, one end of the removed blood vessel is attached to the aorta, and the other end is attached to the coronary artery distal to the atherosclerotic plaque. However, when internal mammary arteries are used, the distal end of the artery is detached from the chest wall and anastomosed to the coronary artery distal to the plaque. A median sternotomy, in which an incision the length of the sternum is made, is commonly required to gain access to the thoracic cavity and expose the heart. As the "new" blood vessels are being engrafted, the patient is typically placed on cardiopulmonary bypass (i.e., heart-lung machine) to maintain appropriate myocardial and systemic perfusion. Alternative surgical approaches for advanced IHD may be used in some settings including "off-pump" CABG (cardi-opulmonary bypass is not required) and minimally invasive CABG (i.e., thorascopic surgery), although these techniques are not the norm. Because of the extremely invasive nature of this surgery, CABG surgery is generally reserved for patients with extensive coronary disease or as a treatment of last resort in patients with symptoms refractory to medical therapy.
Pharmacotherapy to Prevent ACSs and Death Control of Risk Factors
A major component of any IHD treatment plan is control of modifiable risk factors, including dyslipidemia, hypertension, and diabetes. In addition, although not discussed in detail in this chapter, mental depression is common among patients with IHD and increases the risk for cardiac events and death. Thus, patients with IHD should be assessed for depression, and if present, appropriate management of depression should ensue.
Treatment strategies for dyslipidemia and hypertension in the patient with IHD are summarized in the following paragraphs. Visit chapters in this textbook on the management of hypertension and dyslipidemia for further information.
Because lipoprotein metabolism and the pathophysiology of atherosclerosis are closely linked, treatment of dyslipidemias is critical for both primary and secondary prevention of IHD-related cardiac events. In 2001, the Adult Treatment Panel III of the National Cholesterol Education Program issued guidelines for the management of dyslipidemia and recommended an LDL cholesterol goal of less than 100 mg/dL (2.59 mmol/L) for patients with documented IHD or IHD-risk equivalents such as diabetes or other vascular disease.14 Since the publication of these guidelines, new evidence from several primary and secondary prevention trials suggests that there are additional clinical benefits from further reduction in LDL cholesterol.15 In response to this evidence, more aggressive cholesterol-lowering goals were established for patients at high risk for developing IHD-related events, including those with diabetes or known cardiovascular disease. The following modifications were made to national treatment guidelines15,16:
• Statin or other LDL-lowering therapy is indicated along with lifestyle modifications in patients with cardiovascular disease or diabetes and multiple cardiovascular risk factors, regardless of baseline LDL cholesterol.
• Intensity of LDL-lowering therapy should be sufficient to decrease LDL cholesterol by 30% to 40%.
• Goal LDL cholesterol in patients with known clinical cardiovascular disease or diabetes plus one or more cardiovascular risk factors is less than 70 mg/dL (1.81 mmol/L).
Like dyslipidemia, hypertension is a major, modifiable risk factor for the development of IHD and related complications. Unfortunately, awareness, treatment, and control of blood pressure are suboptimal. Aggressive identification and control of hypertension is warranted in patients with IHD to minimize the risk of major adverse cardiac events. Goal blood pressure in patients with IHD is less than 130/80 mm Hg with consideration of reducing blood pressure to less than 120/80 mm Hg in patients with left ventricular dysfunction or heart failure.18 Because of their cardioprotective benefits, P-blockers and ACE inhibitors (or ARBs in ACE-inhibitor-intolerant patients), either alone or in combination, are appropriate for most patients with both hypertension and IHD.
Platelets play a major role in the pathophysiology of ACS. Specifically, platelets adhere to the site of atherosclerotic plaque rupture where they become activated, aggregate, and stimulate thrombus formation and ACS. Thromboxane is a potent platelet activator. Aspirin inhibits cyclooxygenase, an enzyme responsible for the production of thromboxane, thereby inhibiting platelet activation and aggregation. In patients with stable or unstable angina, aspirin has been consistently shown to reduce the risk of major adverse cardiac events, particularly MI.19 Antiplatelet therapy with aspirin should be considered for all patients without contraindications, particularly in patients with a history of MI. Aspirin doses of 75 to 162 mg daily are recommended in patients with or at risk for IHD. ,20 If aspirin is contraindicated (e.g., aspirin allergy) or is not tolerated by the patient, other antiplatelet agents such as clopidogrel should be considered.
Dual antiplatelet therapy with aspirin and a thienopyridine is recommended following PCI with stent placement to prevent stent thrombosis prior to stent endothelializ-ation. Historically, ticlopidine was the thienopyridine agent used in combination with aspirin. However, clopidogrel has essentially replaced ticlopidine due to hematologic toxicity (leukopenia) of ticlopidine and the growing body of evidence supporting the use of clopidogrel. Antiproliferative drugs in drug eluting stents delay endothelializ-ation, and thus a longer period of combination antiplatelet therapy is recommended for drug-eluting stents compared to bare metal stents to prevent thrombosis. Recent guidelines advocate combination antiplatelet therapy for at least 1 month after a bare metal stent and at least 12 months after a drug-eluting stent, although there are some data to support indefinite use of combination antiplatelet therapy after stent place-21
ment. Because of the risk for stent thrombosis with premature discontinuation of dual antiplatelet therapy, it is imperative for clinicians to educate patients on this risk and the need for continuation of combination antiplatelet therapy for the recommended duration.
There are also data to support use of dual antiplatelet therapy in patients with ACS regardless of whether PCI with stent implantation is performed. In this population, the combination of aspirin and clopidogrel was more effective than aspirin alone in
decreasing the risk of death, MI, and stroke. ' For more information regarding the use of dual antiplatelet therapy in the setting of ACS, the reader is referred to the Acute Coronary Syndromes Chapter.
Statins are the preferred drugs to achieve LDL cholesterol goals based on their potency in lowering LDL cholesterol and efficacy in preventing cardiac events. Specifically, over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol with statins is effective for both primary and secondary prevention of IHD-related events.15 Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvastatin. A
recent meta-analysis showed that the risk of major adverse cardiac events is reduced
by 21% with the use of statins in patients at high risk for IHD-related events.
Several studies have investigated whether statins possess pharmacologic properties in addition to their LDL cholesterol-lowering effect that may confer additional bene-
fits in IHD. These studies were prompted by evidence that patients with "normal" LDL cholesterol derived benefit from statins. Statins have been shown to modulate the following characteristics thought to stabilize atherosclerotic plaques and contribute to the cardiovascular risk reduction seen with these drugs:
• Shift LDL cholesterol particle size from predominantly small, dense, highly atherogenic particles to larger, less atherogenic particles.
• Improve endothelial function leading to more effective vasoactive response of the coronary arteries.
• Prevent or inhibit inflammation by lowering C-reactive protein and other inflammatory mediators thought to be involved in atherosclerosis.
• Possibly improving atherosclerotic plaque stability.
In summary, to control risk factors and prevent major adverse cardiac events, statin therapy should be considered in all patients with IHD, particularly in those with elevated low-density lipoprotein cholesterol or diabetes. Statins are potent lipid-
lowering agents, possess non-lipid-lowering effects that may provide additional benefit to patients with IHD, and have been shown to reduce morbidity and mortality in patients with IHD. Based on these benefits, statins are generally considered the drugs of choice in patients with dyslipidemias. Moreover, based on evidence that statins improve outcomes in patients with IHD and "normal" LDL cholesterol concentration, statins should be considered in all patients with IHD at high risk of major adverse cardiac events, regardless of baseline LDL cholesterol.
Angiotensin II is a neurohormone produced primarily in the kidney. It is a potent vasoconstrictor and stimulates the production of aldosterone. Together, angiotensin II and aldosterone increase blood pressure and sodium and water retention (increasing ventricular wall tension), cause endothelial dysfunction, promote blood clot formation, and cause myocardial fibrosis.
ACE inhibitors decrease angiotensin II production and have consistently been shown to decrease morbidity and mortality in patients with heart failure or a history of MI.26,27 A meta-analysis of 22 clinical trials with ACE inhibitors in post-MI patients found that ACE inhibitors reduced 1-year mortality by 16% to 32%, and the
mortality-reducing effects were sustained for up to 4 years. In addition, there is evidence that ACE inhibitors reduce the risk of vascular events in patients with chron-
ic stable angina or risk factors for IHD. ' Specifically, in nearly 10,000 patients with vascular disease (including IHD) or risk factors for vascular disease, such as diabetes, ramipril reduced the risk of death, acute MI, and stroke by 22% compared to
placebo after an average of 5 years of treatment. Similar results have been demonstrated with perindopril in patients with IHD.29
In the absence of contraindications, ACE inhibitors should be considered in all patients with IHD, particularly those who also have hypertension, diabetes mellitus, chronic kidney disease, left ventricular dysfunction, history of MI, or any combination of these. Additionally, ACE inhibitors should also be considered in patients at high risk for developing IHD based on findings from the studies summarized above. ARBs may be used in patients with indications for ACE inhibitors but who cannot tolerate them due to side effects (e.g., chronic cough). ARBs also antagonize the effects of angiotensin II. In one large trial, valsartan was as effective as captopril at reducing morbidity and mortality in post-MI patients.26 However, there are far more data supporting the use of ACE inhibitors in IHD. Therefore, ACE inhibitors should remain first-line in patients with a history of MI, diabetes, chronic kidney disease, or left ventricular dysfunction. The ACE inhibitors and ARBs with indications for patients with or at risk for IHD or IHD-related complications are listed in Table 7-5.
Side effects with ACE inhibitors and ARBs include hyperkalemia, deterioration in renal function, and rarely, angioedema. Serum potassium increases are secondary to aldosterone inhibition and are more likely in the presence of pre-existing renal impairment, diabetes, or concomitant therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), potassium supplements, or potassium-sparing diuretics. Reductions in glomerular filtration may occur during ACE inhibitor or ARB initiation or up-titration due to inhibition of angiotensin II-mediated vasoconstriction of the efferent arteriole. This type of renal impairment is usually temporary and is more common in patients with pre-existing renal dysfunction or unilateral renal artery stenosis. Bilateral renal artery stenosis is a contraindication for ACE inhibitors and ARBs because of the risk for overt renal failure. Angioedema is a potentially life-threatening adverse effect that occurs in less than 1% of ACE inhibitor-treated patients and may also occur with ARBs. Substitution of an ARB for an ACE inhibitor is appropriate for patients who develop a persistent cough with ACE inhibitor therapy, as this cough is believed to be due to accumulation of bradykinin secondary to ACE inhibition. Both ACE inhibitors and ARBs can cause fetal injury and death and are contraindicated in pregnancy.
Table 7-5 Doses of ACE Inhibitors and ARBs Indicated in IHD
Drug_Indications_Usual Dosage in IHD"
Captopril HTM HR post-MI, 6,25-50 rng 3 x daily
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