Chronic Stable Angina

Atherosclerosis

Chronic Stable Angina Pectoris

 

Atherosclerotic disease is the leading cause of death among men and women in Europe, the United States, and worldwide. Previously considered a “western” disease, it is now clear that various peoples of diverse ethnic backgrounds are vulnerable to atherosclerosis. The epidemic of obesity, especially abdominal obesity, escalates the need for appropriate detection and management of high risk individuals. The overwhelming consumption of economic and medical resources necessitates preventive measures in order to decrease the global burden of heart disease. The recent Interheart study, a very large case–control study of acute myocardial infarction in 52 countries, demonstrates that traditional risk factors for coronary heart disease (CHD) account for most of the risk worldwide (over 90%) and include abnormal lipids, smoking, diabetes, hypertension, abdominal obesity, psychosocial factors, diminished consumption of fruits and vegetables, lack of regular alcohol intake, and lack of regular physical activity. The two most potent risk factors worldwide are smoking and dyslipidaemia.  The forefront of primary and secondary prevention of CHD is the management of dyslipidaemia.

 

Patients may underestimate the importance of normalizing lipid levels; counseling and monitoring for adherence to therapy are vital

 

In 1998, heart disease was the leading cause of death in the United States.¹ Elevated serum cholesterol has been shown to increase the risk of coronary artery disease (CAD).² Between 1988 and 1991, approximately 19.5% of persons between the ages of 20 and 74 had total serum cholesterol over 240 mg/dL. Average serum cholesterol in that age group was 205 mg/dL.³ In 1996, the cost of cardiovascular disorders was $151.1 billion.⁴ Studies have shown that prevention of CAD with cholesterol-lowering agents is cost-effective and reduces morbidity and mortality.^5–11

 

See also Adult Treatment Panel III Report on High Blood Cholesterol

A lipid profile including total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and triglycerides should be checked in all adults beginning at age 20, but earlier if the patient is obese or there is a family history of premature atherosclerotic disease or primary lipoprotein abnormalities. Elevated apo-B values may be a more accurate indicator of atherosclerotic risk than LDL alone. However, current guidelines base treatment on LDL values. European guidelines advocate use of the SCORE model and risk charts while US guidelines advocate use of the Framingham risk model and implementation of National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) guidelines based on calculated risk.⁵ Multiple recent trials demonstrate the benefit of more aggressive lipid treatments, especially in very high risk groups such as those with established atherosclerotic disease and uncontrolled risk factors such as metabolic syndrome and diabetes.

 

 

Primary Lipoprotein abnormalities

Disorder	Mechanism	Complication
(Familial) hypertriglyceridaemia	Decreased serum triglycerides removal secondary to decreased LPL activity	Pancreatitis (triglycerides >2000 mg/dl (>22.5 mmol/l))
	Increased hepatic secretion of triglyceride-rich VLDL
(Familial) combined hyperlipidaemia	Increased hepatic secretion of apolipoprotein B containing VLDL and conversion to LDL	CAD, PVD, CVD
	Accumulation of VLDL, LDL, or both, depending on efficiency of their removal
Remnant removal disease (familial dysbetalipoproteinaemia)	Increased secretion of VLDL	PVD, CAD, CVD
	Impaired removal of remnant lipoproteins resulting from homozygosity (e2/e2) or heterozygosity (e2/e3 or e2/e4) for lipoprotein E e2
Familial or polygenic hypercholesterolaemia	Diminished LDL-receptor activity	CAD, occasionally PVD, CVD
	Defective apolipoprotein B that is poorly recognised by LDL receptor
Familial hypoalphalipoproteinaemia (low HDL syndrome)	Diminished apolipoprotein A1 formation	CAD, PVD
	Increased removal of apolipoprotein A1
	ABCA1 deficiency (Tangier’s disease)
	Increased CETP or hepatic lipase activity

Dyslipidemia and Lipoproteins

Lipoproteins are water-soluble spheres that transport lipids through the body. They are classified by their size, function and content of proteins, triglycerides, cholesterol and phospholipids. There are dozens of subtypes of lipoproteins, but only three are routinely monitored:

1)    very low density lipoprotein (VLDL)

2)    low density lipoprotein (LDL); and

3)    high density lipoprotein (HDL) (see TABLE 1).

Total cholesterol is the combination of VLDL, LDL and HDL, using the formula:
Total cholesterol = HDL + LDL + (VLDL/5)

The groups of people who derive the largest benefit from preventive strategies include those with established atherosclerotic disease—CHD, peripheral vascular disease (PVD), cerebrovascular disease and stroke (CVD)—and asymptomatic individuals who are at high risk of developing atherosclerotic disease such as those with multiple risk factors resulting in a 10 year risk CVD mortality of > 5% by the SCORE model, major elevation in one risk factor such as LDL > 6 mmol/l (240 mg/dl), and those with diabetes mellitus which is considered a CHD equivalent. European guidelines also stress that close relatives of patients with early onset atherosclerotic disease are high risk individuals. Therapeutic lifestyle changes—including healthy eating habits, physical activity, and stopping or never smoking—remain an essential aspect of therapy in all individuals regardless of risk. However, lifestyle changes are typically not enough to reach target lipid concentrations.

National guidelines for determining target lipid concentrations are based on underlying risk. The primary goal is LDL lowering because as LDL increases, CHD risk increases. The European SCORE system assesses 10 year risk of total fatal vascular events and not just 10 year risk of CHD (includes coronary death and non-fatal CHD events) like the US Framingham risk score. It incorporates data from pooled cohort studies from 12 European countries. It integrates sex, age, smoking, systolic blood pressure and either total cholesterol or the cholesterol/HDL ratio. Unlike the Framingham risk score, the European SCORE system allows projection of risk to age 60, allowing young adults who may have low 10 year risks but relatively high lifetime risks to estimate near lifetime risk of having a fatal CVD event. This approach is beneficial in a setting of societal increases in waistline and metabolic syndrome, especially for vulnerable populations such as South Asians.

The NCEP/ATP III guidelines identify the following groups as high risk: established atherosclerotic disease (CHD, PVD, and CVD), diabetes, and those with 10 year Framingham risk > 20%. Risk is calculated based on Framingham risk score which incorporates age, total cholesterol, smoking status, HDL, and systolic blood pressure to determine the Framingham 10 year risk of CVD events. Important omissions in both SCORE and the Framingham risk algorithm are risk factors such as positive family history for CHD, impaired glucose tolerance, or hypertriglyceridaemia.

The target LDL value in high risk individuals is < 2.6 mmol/l (100 mg/dl) using SCORE or the Framingham risk algorithm. Moderate risk individuals defined by the Framingham risk algorithm as having 10–20% 10 year risk for CHD events have a target LDL of < 3.4 mmol/l (130 mg/dl). Low risk individuals have < 10% 10 year risk and the target LDL is < 4.1 mmol/l (160 mg/dl). Optimal LDL in very high risk individuals with established atherosclerotic disease and diabetes, ongoing uncontrolled risk factors, and recent unstable angina may benefit from further LDL lowering to a target < 1.8 mmol/l (70 mg/dl).Once a patient’s risk is estimated then a decision to initiate treatment would be made based on estimated CHD risk, co-morbid conditions, contraindications to therapy, and patient’s concerns.

Persons with multiple borderline abnormalities such as young people with abdominal obesity and > 75th centile values of LDL, triglycerides, blood pressure, and/or waist circumference for age and sex will often have low 10 year risk scores by currently advocated risk assessments. Although they may not meet criteria for metabolic syndrome, if their risk factors are not controlled there is an inevitable progression to metabolic syndrome and possibly future diabetes and heart disease, especially if there is a significant family history for these diseases. These people should not be told they are low risk and given false reassurance. It should be emphasised that they are metabolically abnormal and that they have multiple risk factors for heart disease. They should be aggressively counselled to modify diet by decreasing saturated fats and increasing fruits and vegetables, including one to two fatty fish meals per week, increasing physical activity, and stopping smoking. Pharmacological treatment may be considered if behavioural changes do not improve risk profile. However, guidelines should be applied and consideration to long term costs and risk of pharmacological treatment should also be considered before institution of treatment.

 

Each lipoprotein plays a slightly different role in cholesterol metabolism and synthesis (FIGURE 1). Because VLDL is the predominate carrier of triglycerides, many clinicians refer to VLDL as triglycerides (TG). VLDL particles are synthesized by the liver, transport triglycerides to peripheral adipose tissue and eventually are converted to LDL. Lipoprotein lipase is a key enzyme in the conversion of VLDL to LDL and is the target of some cholesterol-lowering medications. Until recently, elevated VLDL (>1,000 mg/dL) was known to be associated only with pancreatitis; however, new evidence links increased triglycerides to atherosclerosis and heart disease.

Pathways of lipid transport : pathways of lipid transport, illustrating cholesterol absorption from the intestine and transport to the liver. Further metabolism results in hepatic cholesterol entering the circulation as very low density lipoprotein (VLDL). Then VLDL is metabolised to remnant lipoproteins after lipoprotein lipase removes triglyceride. Remnant lipoproteins are removed by LDL receptors (LDL-R) or further metabolised to LDL and then removed by these receptors. Cholesterol is transported from peripheral cells to the liver by high density lipoprotein (HDL). Cholesterol is recycled to LDL and VLDL by cholesterol ester transport protein (CETP) or is taken up in the liver by hepatic lipase. Cholesterol is excreted in bile. The points at which the five primary lipoprotein disorders affect lipid metabolism are shown: familial hypertriglyceridaemia (FHTG), familial combined hyperlipidaemia (FCHL), remnant removal disease (RRD, also known as familial dysbetalipoproteinaemia), familial hypercholesterolaemia (FH), and hypoalphalipoproteinaemia.

Cholesterol-rich LDL particles transport cholesterol from the liver to the peripheral tissues. High levels of LDL (referred to as the “bad cholesterol”) are associated with hardening and blockage of the vessels, or atherosclerosis.¹⁵ Atherosclerosis leads to ischemia and damage of coronary tissue. On the other hand, HDL particles transport cholesterol from the peripheral tissues to the liver and essentially act as a scavenger lipoprotein. Patients with high levels of HDL have a lower incidence of CAD.¹⁵ Because of the inverse relationship of HDL (the “good cholesterol”) with CAD, the term dyslipidemia is preferred over “high cholesterol.”

The Thyroid/Cholesterol Connection

Have your patients who are taking lipid-lowering agents been checked for thyroid dysfunction? This may be an important question to ask, according to the American Association of Clinical Endocrinologists (AACE). Thyroid disease is the second most common secondary cause of dyslipidemia, after diet. Hypothyroidism results in decreased clearance of cholesterol from the blood, and correction of the condition may normalize cholesterol levels. FDA and NCEP guidelines both indicate that thyroid dysfunction must be ruled out before initiating standard lipid-lowering agents. Yet in a recent survey by AACE, less than half of the adults who had been diagnosed with dyslipidemia knew if they had ever been tested for thyroid disease.

National Cholesterol Education Program (NCEP)

The Expert Panel on the Detection, Evaluation, and Treatment of Dyslipidemia published the National Cholesterol Education Program (NCEP) Guidelines in 1985 and 1993.¹⁵ The NCEP guidelines are frequently used as the template for the treatment of high cholesterol. The NCEP panel recommends that all adults over 20 years old have their cholesterol checked every 5 years. Treatment of dyslipidemia in patients with no history of CAD is called primary prevention. Secondary prevention is the treatment of dyslipidemia after a patient has been diagnosed with CAD or other atherosclerotic diseases (peripheral vascular disease or cerebral vascular disease). NCEP guidelines for target LDL are based on presence of CAD and risk factors for CAD (TABLES 2 and 3). Since the publication of the NCEP guidelines, there has been a significant amount of debate regarding the benefit of reducing LDL to <100 mg/dL. A reanalysis of the studies that examined the effect of statins on CAD risk, assessed the relationship between the magnitude of LDL reduction and reduction of CAD risk.^16,17 The results are conflicting, and further studies are warranted. In any case, elevated low density lipoprotein levels are still considered the major risk factor in CAD.

There are several drug and nondrug treatment options for dyslipidemia. Patients on any lipid-lowering therapy should be informed that dyslipidemia increases the risk of cardiovascular disease. The importance of adherence to diet and drug therapy should be stressed.

Table 2 Risk Factors for CAD

Age (male >45 years, female >55 years or post menopausal) Family history of premature MI or CHD Diabetes mellitus Cigarette smoking Hypertension High LDL, >160–180 mg/dL HDL <35 mg/dL Negative risk factor: HDL >60 mg/dL

                                                                                                                                                                                 

 

 

 

Lipid therapy is based on the understanding of lipid metabolism. The effects of different drug treatments can be better understood by understanding these pathways. Multiple clinical trials have shown benefit in decreasing CHD “hard” outcomes such as myocardial infarction and death with statin use (including atorvastatin, simvastatin, pravastatin, and lovastatin) in both people with established CHD and those without established CHD. These distinctions are termed primary and secondary prevention, respectively. LDL lowering is still the primary goal in CVD prevention.

 

Management of dyslipidaemias: key points Prevention of coronary heart disease (CHD) includes the detection of dyslipidaemia and treatment of dyslipidaemia based on current guidelines Low density lipoprotein (LDL) reduction via statin therapy is first line treatment because of the many trials that have shown decreased CHD events, including mortality, with different statins Treatment of low high density lipoprotein (HDL) and hypertriglyceridaemia has strong justification as well Appropriate monitoring for toxicity is important when implementing drug therapy in the treatment of dyslipidaemias Lifestyle changes including diet, regular exercise, and smoking cessation are critical in the treatment of dyslipidaemias and heart disease prevention Physicians need to educate patients about the benefits of CHD prevention as well as possible risks of pharmacological treatment

 
Lifestyle Modifications

Although obesity and sedentary lifestyles are not listed as CAD risk factors, their presence will increase the likelihood of other risk factors (e.g., diabetes, elevated LDL, low HDL, hypertension). In order to reduce the risk of CAD, interventions aimed at increasing exercise and weight reduction in obese patients should be employed. Even modest weight reduction will improve a patient’s lipid profile and reduce the risk of hypertension, dyslipidemia and diabetes. Exercise also has been shown to have a positive effect on lipid profile by increasing HDL. Smokers with dyslipidemia should be counseled on the added risk of cigarette smoking and referred to a smoking cessation program.

The NCEP guidelines include specific recommendations for diet therapy to reduce intake of saturated fats and cholesterol.² Diet therapy has been shown to lower total serum cholesterol between 5% and 10%.¹⁸ NCEP diet therapy is broken down into Step I and Step II diets (TABLE 4). Step II diet has a lower saturated fat allowance (7% of total calories vs. 10% in Step I). Increased saturated fat intake has a more adverse effect on lipid profile than do monounsaturated and polyunsaturated fats.¹⁸ TABLE 5 lists common sources of these fats. TABLE 6 lists some simple recommendations for decreasing fat intake. In order, to ensure successful implementation of these diets, it is imperative that patients be referred to a dietitian.

 

Determining the optimal diet in patients with dyslipidaemia is challenging. The ideal goal is to improve the metabolic profile in anyone with a dyslipidaemia and induce weight loss in those who are overweight. Traditional standards of BMI may not be as helpful in guiding appropriate weight loss, and waist circumference may be a better standard. The metabolic syndrome includes abdominal obesity and two of the following abnormalities: high triglycerides ( 150 mg/dl (1.69 mmol/l) or on triglyceride treatment), low HDL ( 40 mg/dl (1.02 mmol/l) for men and 50 mg/dl (1.28 mmol/l) for women or on HDL treatment), elevated blood pressure ( 130/85 mm Hg or on antihypertensive treatment), and elevated fasting blood glucose 100 mg/dl (5.5 mmol/l) (includes diabetes). The metabolic syndrome definition of abdominal obesity is traditionally 40 inches (100 cm) in men and 35 inches (88 cm) in women. However, these numbers may be too high when applied to, for example, Asians, Hispanics, Native Americans, and South Asians. Thus the definition of abdominal obesity is population specific

 

 

 

 

A flow chart that aids the practitioner in the decision making process in determining treatment in moderate and high risk individuals. Determining treatment in moderate and high risk individuals for coronary heart disease. BMI, body mass index; CHD, coronary heart disease; CVD, cerebrovascular disease, stroke; DM, diabetes mellitus; HDL, high density lipoprotein; LDL, low density lipoprotein; PVD, peripheral vascular disease:

 

 

HMG CoA Reductase Inhibitors

Lovastatin (Mevacor) was the first 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitor approved in the United States (in 1989). Since then, five others have been approved: pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor) and cerivastatin (Baycol). The statins are the most commonly prescribed cholesterol-lowering medications. HMG CoA reductase is an enzyme that catalyzes the rate-limiting step in hepatic cholesterol synthesis. Inhibition of this enzyme halts the liver’s biosynthesis of cholesterol. Reduction in cholesterol levels causes the liver to increase the number of LDL receptors on the surface of hepatocytes and LDL clearance from the serum increases. In summary, statins lower cholesterol synthesis and increase LDL catabolism.

The effects of statins on the lipid profile vary according to the particular agent used (TABLE 7). Several studies have examined the effectiveness of statins in prevention of coronary morbidity and mortality. In a controlled, double-blind, multicenter, 5.4-year trial, 4,444 Scandinavian patients with cardiovascular disease and dyslipidemia were randomized to treatment with 20 mg of simvastatin or placebo.⁶ The simvastatin-treated group had an average of 25%, 35%, and 10% reduction in total cholesterol, LDL and TG, respectively (p > 0.05 for all groups). Twelve percent of the placebo group died, versus 8% of the simvastatin group. The statistical analysis revealed that 95% of the patients treated with simvastatin had a 58%–85% chance of living longer than the placebo group (p = 0.003).
The Cholesterol and Recurrent Events (CARE) study was a randomized, double-blind, multicenter trial with 4,159 patients with dyslipidemia and history of myocardial infarction.¹⁰ Patients were randomized to placebo or 40 mg of pravastatin for five years. Patients who were treated with pravastatin had a 25% lower incidence in myocardial infarction (p = 0.006) and 31% lower incidence in stroke (p = 0.03) compared to placebo-treated patients.

 

 

The West of Scotland Coronary Prevention study was a primary prevention trial that studied 6,595 men between 45 and 60 years old with dyslipidemia but no history of CAD.⁸ The patients were randomized to a double-blind treatment with either pravastatin 40 mg or placebo for five years. Pravastatin-treated patients had a 31% reduction in cardiovascular events (p = 0.001), 32% reduction in cardiovascular deaths (p = 0.033) and 22% reduction in overall deaths (p = 0.051).
In general, the statins are well tolerated. In most clinical studies, less than 4% of patients discontinue these agents because of side effects.^6,8,10,23 The most common side effects include increased liver function enzymes (1%–2%), increased creatine kinase (0.1%–5%), myopathy (or muscle damage) (0%–2.7%), headaches and insomnia (0.5%–10%), and GI upset (<2%).^19-23 The incidence of CNS side effects may be slightly higher with lovastatin and simvastatin because they cross the blood-brain barrier.²³ Rhabdomyolysis (potentially deadly muscle destruction) is a rare but serious side effect of statin therapy. Muscle pain and increased creatine kinase (above 10 times normal) are signs of potential rhabdomyolysis. Patients with complaints of muscle weakness or pain should have their creatine kinase levels checked. If the levels are greater than 10 times normal, the drug should be discontinued. If the offending agent was a hydrophilic statin (lovastatin, cerivastatin or pravastatin) then a trial of a lipophilic agent (simvastatin, atrovastatin or fluvastatin) may be warranted, although further studies are needed to prove this.²³

Cyclosporine, erythromycin, nefazodone, azole antifungals, and fibric acid derivatives (clofibrate and gemfibrozil) have all been reported to increase the serum concentration of statins and the risk of myopathy when used concomitantly. Patients taking atorvastatin, cerivastatin, fluvastatin, or pravastatin and cyclosporine, erythromycin, nefazodone, azole antifungals, or fibric acid derivatives should be closely monitored for elevations in CPK (creatine protein kinase) and muscle pain. Metabolism of lovastatin and simvastatin is particularly sensitive to drug interactions; combining lovastatin or simvastatin with cyclosporine, erythromycin, nefazodone, azole antifungals, or fibric acid derivatives should be avoided. Each statin has a slightly different metabolic pathway, and the dependence for metabolism of a specific cytochrome isoenzyme is different for each statin. Therefore, each statin does not have an identical drug interaction profile. Concomitant use of niacin and statins may increase the risk of hepatotoxicity compared to when these agents are used alone.

Statins are effective in lowering serum cholesterol and have been shown to prevent coronary vascular events. However, these agents can be be cost-prohibitive (average wholesale price ranges from $33 to $125 per month) to some patients. This makes it essential to explain the benefits of drug therapy in prevention of heart disease.

All of the statins, except atorvastatin and lovastatin, should be administered in the evening because of increased nocturnal hepatic production of cholesterol. Cerivastatin, fluvastatin, pravastatin and simvastatin should be taken at bedtime without regard to meals. Lovastatin should be taken with dinner. Atorvastatin can be taken at any time of the day because its effects do not seem to vary with administration times. When taking any statin, patients should report any unexplained muscle aches and pains to their primary care providers.

LDL lowering treatment

Statins are competitive inhibitors of HMG-CoA reductase, the key rate limiting enzyme involved in cholesterol synthesis. They decrease primarily LDL cholesterol concentrations by upregulating LDL receptor activity and decreasing entry of LDL into the circulation. Statins also favourably decrease fibrinogen concentrations and viscosity, increase activation of endothelial nitric oxide synthase, decrease C-reactive protein (CRP) independent of LDL lowering effects, modestly decrease triglycerides, and modestly increase HDL. Statins should be given in the evening because endogenous cholesterol synthesis is higher at night. Different potencies of statins exist and determining drug choice and dosage is established primarily by the amount of LDL reductioeeded, the safety profile of the drug, and concomitant drug usage. Tissue penetration may be less with the hydrophilic pravastatin and rosuvastatin. All other statins are lipophilic. Table below summarises the expected reduction in LDL with various statins.

 

Low density lipoprotein cholesterol (LDL) reduction by percentage change according to statin and daily dose (summary estimates from 164 randomised placebo controlled trials)

 

Statin   Percentage reduction in LDL* 5 mg 10 mg 20 mg 40 mg 80 mg   Lovastatin (Mevacor)   21% 29% 37% 45% Pravastatin (Pravachol) 15% 20% 24% 29% 33% Fluvastatin (Lescol) 10% 15% 21% 27% 33% Simvastatin (Zocor) 23% 27% 32% 37% 42% Atorvastatin (Lipitor) 31% 37% 43% 49% 55% Rosuvastatin (Crestor) 38% 43% 48% 53% 58%

Monitoring for statin toxicity is very important. Patients need to be educated about possible symptoms that may indicate myositis or liver dysfunction. These include new muscle aches which may signify myositis. Symptoms of fatigue, sluggishness, anorexia, nausea, and weight loss may indicate hepatitis. Right upper quadrant (RUQ) pain and jaundice are not common. The major risks of statin use are myositis and rarely rhabdomyolysis and perturbations in liver function tests (LFTs). Liver failure is very rare with statin use alone. The incidence of LFT elevations > 3x the upper limit of normal is approximately 0.5–2%. Elevation in LFTs is dose dependent but can be idiosyncratic. Baseline LFTs should be checked in patients and repeated 4–6 weeks after initiation of statin, any significant change in statin dosage, or change to another statin, or after initiation of any medication that may cause change in the metabolism of statins by the liver. A mild to moderate increase in LFTs (< 3x upper limit of normal) is not a contraindication to initiate or continue statin use, but LFTs should be followed very closely. In those with pre-existing liver disease, consultation with the patient’s gastroenterologist/hepatologist may be prudent if statin (fibrate or niacin) treatment needs to be started. If significant LFT elevation > 3x upper limit of normal occurs then statin dose should be decreased or discontinued.

Risk factors for statin toxicity include older age, females, small frail frame, multisystem organ disease, multiple medications, steroid use, excessive alcohol intake, and drinking > 1 litre of grapefruit juice a day. Drugs that inhibit cytochrome P-450 3A4 or 2C9 can increase serum statin concentrations, increasing risk of toxicity. Examples of these drugs include but are not limited to nicotinic acid, cyclosporine, azole antifungals, macrolide antibiotics, HIV protease inhibitors, verapamil, amiodarone, and nefazadone. Fibrates such as gemfibrozil raise statin concentrations by inhibiting the glucuronidation of the statin drug. This is not an exhaustive list and the authors suggest pharmacological consultation with initiation of statins or other lipid lowering treatments in patients on medications that may put them at risk for statin toxicity.

Myositis is another important concern. Patients often have joint or muscle complaints that are ongoing. Distinguishing new symptoms that may suggest myositis is difficult. Education of patients at onset of therapy will provide patients with a time reference so that accurate detection of symptoms is more feasible. In addition to checking baseline LFTs, determining baseline creatine phosphokinase (CPK) is helpful. Elevations in CPK in asymptomatic individuals before initiation of statin treatment is common and may be a normal variant (African Americans often have elevated CPK) or may be secondary to hypothyroidism (check thyroid stimulating hormone) or possibly secondary to pre-existing myopathy of another aetiology such as dermatomyositis. If patients develop symptoms indicative of myositis, CPK should be checked. Drug treatment should be discontinued if CPK elevation is > 10x upper limits of normal. It is not clear what to do for lesser CPK elevations and it is reasonable to decrease dosage to see if symptoms abate. If symptoms continue then cessation of drug is appropriate. If CPK is not elevated from baseline but symptoms continue, aldolase may be a more specific test to identify muscle damage. If no laboratory abnormalities are found but symptoms cannot be tolerated by the patient (a frequent occurrence) then treatment should be discontinued. If toxicity develops, it is reasonable to rechallenge patients with a different statin. Often rechallenging with a hydrophilic statin such as pravastatin or rosuvastatin at a low dose may prove beneficial. Again, close monitoring of LFTs and/or CPK is imperative if previous abnormalities existed.

Other adverse effects of statins include rash, peripheral neuropathy, insomnia, and difficulty sleeping or concentrating. Statins are contraindicated in pregnancy and in breast feeding mothers as they are known to be teratogenic, with several different abnormalities reported such as limb dysplasias in the fetus. Physicians need to counsel women of child-bearing potential of this risk.

Statin extenders that decrease LDL cholesterol effectively include bile acid-binding resins and inhibitors of cholesterol absorption. Bile acid-binding resins bind bile acids in the intestine and disrupt the enterohepatic circulation of bile acids and thus increase the conversion of cholesterol into bile acids in the liver. They are second line agents to statins. Resins are not an effective alternative in persons with hypertriglyceridaemia as well since they increase cholesterol synthesis and increase VLDL triglyceride secretion into the circulation. Available resins include cholestyramine, colsevelam and colestipol. Important adverse events include abdominal fullness, gas and constipation. In children and patients with renal failure cholestyramine can cause hyperchloraemic acidosis. Absorption of fat soluble vitamins may be decreased. The resins can bind polar compounds such as warfarin, digoxin, thyroxin, thiazides, and statins. Giving medications one hour before or four hours after resin administration may decrease this effect.

Another second line treatment for raised LDL is ezetimibe. It is most often used in combination with statins for additional LDL lowering. Ezetimibe may be used as monotherapy in people who do not tolerate statins, but long term reductions in atherosclerotic events are not yet demonstrated. Ezetimibe inhibits absorption of cholesterol at the brush border of the small intestine, decreasing cholesterol delivery to the liver. This effect results in decreased total cholesterol, LDL, apo B, and triglycerides, and modest increases of HDL.

Bile Acid Sequestrants

Bile acid sequestrants, cholestyramine and colestipol, are resins that bind cholesterol-rich bile and increase its elimination, resulting in lower cholesterol levels. As cholesterol levels decline, the liver produces more LDL receptors. LDL clearance increases, and LDL levels drop. Bile acid sequestrants are an appropriate choice for treatment when elevated LDL is the primary abnormality. Resins can increase triglyceride levels initially, and VLDL levels should be monitored closely (TABLE 7).

The Lipid Research Clinics Coronary Prevention Trial is the largest trial to date (N = 3,806) to examine the effectiveness of bile acid sequestrants (cholestyramine) in lowering cholesterol and preventing CAD. Patients were randomized to receive either 24 g per day of cholestyramine or placebo. After 7.4 years, the cholestyramine-treated group had a 19% reduction in risk of cardiovascular death and nonfatal myocardial infarction. The cholestyramine group also had 20% less angina and 21% fewer patients who needed a coronary artery bypass graft.

Many patients with dyslipidemia also have co-morbid diseases (e.g., hypertension and diabetes), making the use of other drugs essential. The long list of drugs that interact with resins (TABLE 8) complicates the use of this medication. Resins bind to most drugs in the GI tract and prevent absorption. These drug interactions can be minimized by counseling the patient to take other medications two hours before or four hours after taking a resin.

Table 8 Drugs Whose Absorption is Decreased by Bile Acid Sequestrants
• acetaminophen • amiodarone • carbamazepine • desipramine • diclofenac • digoxin	• fluvastatin • furosemide • gemfibrozil • glipizide • hydrocortisone • imipramine	• iron • loperamide • lorazepam • lovastatin • methotrexate • metronidazole	• piroxicam • pravastatin • propranolol • simvastatin • tetracycline • thiazides	• thyroid     hormones • tolbutamide • valproic acid • warfarin

GI upset, including flatulence, bloating and constipation, is a common side effect of resins. These side effects usually diminish with continued use. The powder should be dissolved in an 8 oz. glass of fluid and taken immediately. The unpalatable taste and texture can be reduced by dissolving the powder in juice (orange or grape juice) and vigorously stirring. Patients with a history of constipation or who are prone to constipation (e.g., the elderly) should be instructed to increase water and fiber intake when they are started on resins. A teaspoon of bulk-forming laxative mixed with the resin may attenuate the resin-induced constipation. If necessary, a stool softener may also be recommended.

Nicotinic Acid Derivatives (Niacin)

Niacin (vitamin B₃) decreases VLDL by increasing the activity of lipoprotein lipase, a key enzyme in removal of triglycerides. Niacin’s effect on LDL is the result of decreased VLDL (LDL precursor) and increased clearance of LDL precursors by the liver. Nicotinic acid also increases HDL but the mechanism by which it does so is not fully understood.²⁶ Nicotinic acid derivatives are indicated for the treatment of elevated LDL and/or VLDL.

The efficacy of niacin in preventing coronary events has been demonstrated in the Fifteen Year Mortality in Coronary Drug Patients study.²⁷ In this trial, 8,341 patients with dyslipidemia were assigned to one of five treatment groups: estrogens, clofibrate, dextrothyroxine, niacin or placebo. After a 15-year follow-up, the niacin-treated group had an 11% lower mortality rate than the placebo group (p = 0.0004). The authors concluded that the average long-term survival benefit was 1.6 years.

Side effects are the major limitation to the use of niacin. The most common are flushing and itching, which usually occur within two hours after administration. GI upset and dizziness are also seen with niacin therapy.²⁸ The cutaneous side effects have been reported to occur in 60%–80% of patients.^29,30 Flushing and pruritus diminish with continued therapy; however, administration of aspirin 81–325 mg 30 minutes before the niacin may decrease the severity of or prevent the flushing. Aspirin premedication should be encouraged for all patients without contraindications to aspirin. Cutaneous reactions to niacin can also be reduced with slow dose titration by 100 mg/week to a target dose of 2 g/day.³⁰ Taking niacin with food may slow absorption and decrease GI and cutaneous side effects.

Between 1% and 2% of patients may have increased liver enzymes with niacin treatment. This side effect is seen mostly when sustained-release products are used.^31,32 Therefore, regular-release niacin should be recommended. Although concomitant administration of statins or fibric acid derivatives with niacin has been shown to increase the risk of hepatotoxic reactions,²⁵ it may be necessary to use multiple agents in patients with very high or refractory LDL. When the use of niacin with a statin or fibric acid derivative is necessary, it is important to monitor liver function enzymes frequently. Niacin also has an adverse effect on uric acid and blood glucose levels, and may exacerbate peptic ulcer disease. Patients with uncontrolled hyperuricemia, gout, peptic ulcer disease and diabetes should avoid using niacin.^29,31,32 Despite many possible adverse effects, niacin treatment has been well tolerated. In one study, over 70% of patients started oiacin tolerated the medication and were able to continue therapy.³⁰

In order to ensure adherence to niacin therapy, patient education is imperative. Patients should be warned of the cutaneous reactions that can occur. Because dizziness is common, patients should be told not to drive or operate heavy machinery after the first time they take niacin, until they know how the agent will affect them. Both regular-release and sustained-release products are available without a prescription. Nicotinamide (niacinamide) does not have hypolipidemic effects and should not be substituted for niacin.

Low HDL is often associated with combined hyperlipidaemia and metabolic syndrome but can occur in isolation. Regular aerobic exercise, weight loss (especially in abdominally obese individuals), moderate alcohol consumption, and smoking cessation all have modest effects on improving HDL. Statins increase HDL by 10% on average. Niacin increases HDL up to 20–35%. Niacin increases HDL by inhibiting hepatic uptake of apolipoprotein A-1 and increases plasma preß HDL cholesterol concentrations. The Coronary Drug Project demonstrated a significant reduction in the incidence of myocardial infarction after five years of niacin treatment among men with a history of myocardial infarction, and death after 15 years of treatment. The side effects of niacin treatment include cutaneous flushing which is the most common reason for discontinuation. Other side effects include dyspepsia, elevation of plasma glucose, and elevation of plasma uric acid concentrations. Despite the modest elevation of glucose seen with niacin it can be used in diabetics as indicated. Flushing can be minimised by taking niacin with a bedtime snack, 30 minutes after aspirin, or with an extended release formulation. It is prudent to start at low dose and escalate gradually. Niacin hepatoxicity can be subtle and patients may complain of nausea and anorexia. LFTs may be elevated and a clue may be unexpected lowering of LDL.

Cholesterol ester transfer protein (CETP) inhibitors are now being tested in clinical trials and are not currently available. Their primary action is transfer of cholesteryl esters from HDL to VLDL and LDL in exchange for triglyceride. HDL increases because of delayed catabolism of apolipoprotein A-1 and A-II and thus increases reverse cholesterol transport.

Fibric Acid Derivatives

Currently, there are three FDA-approved fibric acid derivatives in the United States: gemfibrozil (Lopid), clofibrate (Atromid) and micronized fenofibrate (Tricor). Tricor was approved in February 1998. Fibric acid derivatives decrease LDL and VLDL and increase HDL. The specific mechanism of action of these agents is not completely understood. It appears that these agents lower triglycerides by increasing the activation of lipoprotein lipase, which is a key enzyme in the lipolysis of VLDL, and inhibiting hepatic synthesis of VLDL. HDL is increased because these agents increase the transcription of genes that code for important HDL proteins. Finally, fibric acid derivatives decrease LDL by increasing LDL’s affinity for the hepatic receptor, resulting in increased clearance of LDL.^33,34

Fibric acid derivatives’ profound effect on VLDL is why they primarily are used when elevated VLDL is the major disorder. Besides lowering VLDL, fibric acid derivatives may also lower LDL. The Helsinki Heart Study was a randomized, controlled study that compared gemfibrozil (600 mg twice a day) to placebo in 4,081 patients with dyslipidemia but no history of CAD. The gemfibrozil group had a 10% increase in HDL, a 43% decrease in TG, and a 10% decrease in LDL compared to placebo-treated patients, who had virtually no changes in their lipid profiles. After a 60-month follow-up, the gemfibrozil group had a 34% reduction in cardiac events (p = 0.02).³⁵

In general, fibric acid derivatives are well tolerated. The most common side effect was rash, which occurred in 6% of patients receiving the medication. Gemfibrozil and fenofibrate have been reported to cause an increase in liver function test in approximately 8%–10% of patients.^34,36 Both fibric acid derivatives can cause myopathy and rhabdomyolysis; muscle pain and creatine kinase (a product of muscle breakdown) should be monitored routinely. Because an increased incidence of rhabdomyolysis also has been reported with lovastatin, caution should be exercised when statins and fibric acid derivatives are used concomitantly. Lovastatin or pravastatin and gemfibrozil should not be used together because of high risk of rhabdomyolysis. When gemfibrozil therapy is initiated, patients should be instructed to report any unexplained muscle pain or weakness to their primary care provider. To increase absorption of gemfibrozil, patients should take it 30 minutes prior to meals.

Fibric acid derivatives increase the effectiveness of warfarin; therefore, the dose of warfarin should be reduced. Prothrombin time and international normalized ratio (INR) should be monitored when warfarin-treated patients are started on fibric acid derivatives.

Combination Therapy

Some patients may require a higher reduction in LDL than one agent can achieve. In these incidences, the patient may require additional lipid-lowering agents. Cholestyramine, niacin and gemfibrozil can be used in combination with any statin except lovastatin.^25,37 Pravastatin and lovastatin should not be used in combination with gemfibrozil because of increased risk of rhabdomyolysis. When using other statins in combination with gemfibrozil, creatine kinase levels and signs of myopathy should be monitored. When statins are combined with niacin, there may be an increased incidence of side effects, such as liver damage and myopathy. In general, combination therapy is safe, but patients who are treated with both a statin and gemfibrozil need to have liver function enzymes and creatine kinase levels checked regularly.

The treatment of elevated triglycerides may be warranted. Clearly triglyceride values > 11.3 mmol/l (> 1000 mg/dl) require treatment to avoid pancreatitis. Lower values may also warrant treatment, especially in those with combined hyperlipidaemia (associated with modest elevations of LDL that are small and dense and low HDL). This atherogenic profile results in increased risk of premature CHD. The Copenhagen male study, an eight year prospective study, demonstrated that men in the highest tertile of serum triglycerides had a significantly higher cumulative incidence and relative risk of CHD (2.2) compared with men in the lowest tertile. Treatment of hypertriglyceridaemia with gemfibrozil has decreased coronary events in men with CHD. Fenofibrate and bezafibrate treatment has also shown similar results. Fibrates, however, have not been shown to decrease all cause mortality.

Initial treatment of hypertriglyceridaemia involves decreasing caloric intake by decreasing fat and intake of simple sugars. In diabetic considered. Fibrates activate the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR-) resulting in up-regulation patients, glucose control can decrease triglycerides. If triglycerides remain elevated then treatment with fibrates should be of LDL cholesterol receptor and apolipoprotein A genes and down-regulation of the expression of the apolipoprotein CII gene. They increase fatty acid oxidation in the liver and decrease secretion of triglyceride-rich lipoproteins. Important adverse events with fibrates include gastrointestinal symptoms (especially gemfibrozil), erectile dysfunction (less with fenofibrate), myositis and hepatitis. Myositis risk is increased in patients with renal failure. Fibrates also increase biliary cholesterol concentrations and can cause gallstones.

Fish oil containing eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6) also decreases serum triglycerides. The precise mechanism is not well understood. Supplementation with 1.52 g/day of DHA in men and women with below average values of HDL raised LDL cholesterol but decreased triglycerides, triglyceride/HDL ratio, and the fraction of LDL cholesterol carried by small, dense particles. The American Heart Association recommends 2–4 g of fish oil supplementation daily under physician supervision in people with significant elevation of triglycerides. Adverse reactions of fish oil include LFT abnormalities and a theoretical increased risk of bleeding.

Conclusion

Dyslipidemia, defined as elevated LDL and VLDL and low HDL, has been shown to increase the risk of CAD.² Currently, the strategies to normalize lipid levels include lifestyle modifications and drug treatment. Statins, fibric acid derivatives, niacin and resins have all been shown to be safe and effective means for lowering cholesterol. Patients may underestimate the importance of cholesterol reduction and may not be adherent to diet and drug therapy. Pharmacists can be instrumental in improving adherence to therapy by screening the drug profile for frequency of refills and counseling on compliance with medication and diet.

Stable Angina Pectoris

See also European Guidelines on the Management of Stable Angina Pectoris

The Clinical Problem

The diagnosis of chronic stable angina pectoris includes predictable and reproducible left anterior chest discomfort after physical activity, emotional stress, or both; symptoms are typically worse in cold weather or after meals and are relieved by rest or sublingual nitroglycerin. The presence of one or more obstructions in major coronary arteries is likely; the severity of stenosis is usually greater than 70 percent.

Pathophysiology

Angina occurs when there is regional myocardial ischemia caused by inadequate coronary perfusion and is usually but not always induced by increases in myocardial oxygen requirements. Cardinal features of chronic stable angina include complete reversibility of the symptoms and repetitiveness of the anginal attacks over time, typically months to years. New, prolonged, or recent-onset symptoms are characteristic of unstable angina. Coexisting conditions, such as poorly controlled hypertension, anemia, or thyrotoxicosis, can precipitate or accentuate angina.

As coronary atherosclerosis progresses, there is deposition of plaque external to the lumen of the artery; the plaque may extend eccentrically and outward without compromising the lumen (Figure 1). Thus, stress testing or angiography may not suggest coronary disease, even in the presence of significant atherosclerosis. As atherosclerosis worsens, encroachment of the plaque mass into the lumen can result in hemodynamic obstruction and angina¹ (Figure 1). Disordered endothelial vasomotor function of the coronary arteries is common in patients with angina and results in diminished vasodilatation or even vasoconstriction in response to various stimuli, including exercise.^5,6 Occasionally, patients with severe aortic-valve disease or hypertrophic cardiomyopathy have angina-like chest pain in the absence of overt coronary disease.

 

Figure 1. Typical Progression of Coronary Atherosclerosis.

As the plaque burden increases, the atherosclerotic mass tends to stay external to the lumen, which allows the diameter of the lumen to be maintained; this is known as the Glagov effect, or positive remodeling.¹ As plaque encroaches into the lumen, the coronary artery diameter decreases. Myocardial ischemia results from a discordant ratio of coronary blood supply to myocardial oxygen consumption. Luminal narrowing of more than 65 to 75 percent may result in transient ischemia and angina. In acute coronary syndromes, vulnerable plaque is a more important factor than is the degree of stenosis; acute coronary events result from ulceration or erosion of the fibrous cap, with subsequent intraluminal thrombosis.^2,3 Vulnerable plaque within the vessel wall may not be obstructive and thus may remain clinically silent until it causes rupture and associated consequences.

Classification of Angina Pectoris

Chest pain is characterized as classic, or typical, angina; as atypical angina, which includes symptoms that have some but not all the features of angina; and as nonanginal chest pain, which has none of the features of angina (Table 1).⁷ Chest pain that occurs during rest or at night⁸ is well described in persons with chronic stable angina, particularly women.^9,10,11

Atypical presentations of angina are more common in women than in men. Women with ischemia are more likely than men to report variable pain thresholds, inframammary pain, palpitations, or sharp, stabbing pain.^12,13 Overall, chest pain in women is quite common and usually is not due to coronary artery disease.^9,10,13 Data from the Women’s Ischemia Syndrome Evaluation initiative of the National Heart, Lung, and Blood Institute indicate that many women with anginal symptoms have inducible ischemia and a reduced coronary flow reserve yet no significant obstruction on coronary angiography.^9,10,13 Atypical presentations of angina are also more frequent in older patients (who often have exertional dyspnea, weakness, or sweating) than in younger patients and in patients with diabetes (who often have atypical or even silent ischemic episodes) than in those without diabetes; a high level of suspicion for coronary disease is needed in these groups. The severity of angina should be assessed to aid in management decisions (Table 2). However, there is no direct correlation between the class of angina and the severity of coronary artery disease as determined on angiography.⁷

 

Strategies and Evidence

Diagnostic Strategies

            Stress Testing

Various diagnostic tests are available for the evaluation of suspected coronary disease.¹⁴ Previous Clinical Practice articles in the Journal have focused ooninvasive testing for coronary artery disease.^15,16 Table 3 summarizes common stress-testing methods. Adults with typical or atypical features of chest pain, especially those with major risk factors for coronary artery disease, should undergo stress testing. False positive and false negative exercise tests occur in up to 20 to 30 percent of persons (more commonly in women); coronary angiography is ofteecessary to resolve equivocal test results. Noninvasive testing may provide useful additional prognostic information, such as total exercise time, the inducibility of left ventricular dysfunction, blood-pressure and heart-rate responses, and, most important, the degree of myocardial ischemia.^14,15,16 In general, poor aerobic performance and disordered heart-rate or blood-pressure responses increase the likelihood of subsequent clinical events.

Coronary Angiography

Coronary angiography remains the diagnostic gold standard for obstructive coronary artery disease, but it may miss extraluminal plaque related to coronary remodeling¹ (Figure 1). Indications for angiography include poorly controlled symptoms; abnormal results on stress testing, particularly with a substantial burden of ischemia (e.g., 1 mm or more of ST-segment depression); ischemia at a low workload (below 5 to 6 metabolic equivalents); large, inducible single or multiple wall-motion abnormalities; and substantial nuclear-perfusion defects. Atypical chest pain or inconclusive or discordant test results occasionally warrant the use of angiography. Intermediate-grade coronary obstructions (e.g., 50 to 70 percent stenosis) may require additional evaluation, such as assessment of coronary flow reserve. Suspected vasospastic or microvascular angina requires additional specialized testing.

Cardiac Biomarkers

Elevated levels of high-sensitivity C-reactive protein¹⁷ and other markers, including braiatriuretic peptide,¹⁸ have prognostic value with respect to cardiovascular events in patients with stable angina or asymptomatic coronary artery disease. However, the clinical utility of such testing remains uncertain.

Therapy

It is useful to classify therapeutic drugs into two categories: antianginal (anti-ischemic) agents and vasculoprotective agents. Although medications for angina are widely used (Table 4), therapy to slow the progression of coronary artery disease, to induce the stabilization of plaque, or to do both is a newer concept (Table 5),^19,20,21 and these forms of treatment are underprescribed.

 

         Antianginal Agents

All antianginal drugs — nitrates, beta-adrenergic blockers, and calcium-channel blockers — have been shown to prolong the duration of exercise before the onset of angina and ST-segment depression as well as to decrease the frequency of angina.^22,23,24 Treadmill performance typically increases by 30 to 60 seconds with antianginal drugs as compared with performance with placebo. However, none of these agents have been shown to prevent myocardial infarction or death from coronary disease in patients being treated specifically for chronic stable angina.

Head-to-head comparative trials have not demonstrated that any single class of drugs has greater antianginal efficacy than the others.^22,23,24 Thus, it is reasonable to begin therapy with agents from any of the three groups.

Beta-blockers work primarily by decreasing myocardial oxygen consumption through reductions in heart rate, blood pressure, and myocardial contractility. Although beta-blockers have not been shown to reduce the rate of coronary events or mortality specifically in patients with chronic stable angina, they are identified as class I drugs (i.e., there is evidence or general agreement that they are useful and effective), according to the 2002 American College of Cardiology–American Heart Association guidelines for the management of stable angina.²⁴ This classification is based on older trials showing that these agents prolong survival after myocardial infarction and on recent data showing that they have a similar benefit after primary angioplasty for acute non–ST-elevation myocardial infarction.²⁵ There have beeo large trials assessing the effects of beta-blockers on survival or on rates of coronary events in patients with chronic stable angina. The side effects associated with beta-blockers (Table 4) are often overemphasized; these drugs can be used effectively in many patients with chronic obstructive pulmonary disease or peripheral vascular disease.²⁶

Calcium antagonists dilate coronary and systemic arteries, increase coronary blood flow, and decrease myocardial oxygen consumption. Although the safety of long-acting calcium-channel blockers has been questioned, data from ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial)²⁷ and the results of a recent meta-analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration²⁸ indicate that the use of these drugs for hypertension does not increase morbidity or mortality.

Nitrates dilate systemic and coronary arteries, including some coronary stenoses, and particularly the systemic veins; venous pooling of blood decreases cardiac work and chamber size. Sublingual or oral spray nitroglycerin relieves acute episodes of angina within 5 to 10 minutes; prophylactic use before activity can be helpful in persons with frequent angina. Whereas long-acting nitrates decrease angina and prolong exercise performance, experimental data and data from catheterization laboratories suggest that nitrates increase vascular oxidative stress and may induce paradoxical coronary arterial vasoconstriction.²⁹ Both appear to contribute to the development of nitrate tolerance.^30,31 Prevention of tolerance requires an intermittent dosing strategy, with a nitrate-free interval of 12 to 14 hours (Table 4). Phosphodiesterase type 5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil) and nitrates should not be used within 24 hours of one another because of the potential for serious hypotension.

            Combination Therapy

Underdosing with antianginal agents is common. Even when the dosage is appropriate, physicians should anticipate the need for treatment with two or three agents in many patients.^22,24 Certain drug combinations are recommended, and others should be avoided because of potential hypotension or bradycardia (Table 4). Data from randomized clinical trials support the efficacy of combined therapy with two drugs but provide less support for the use of three agents together.

            Vasculoprotective Therapy

There is considerable evidence that lifestyle changes and pharmacologic therapy may reduce the progression of atherosclerosis, stabilize plaque, or both in chronic stable angina.^19,21,24,32 Aggressive interventions are warranted to control all cardiovascular risk factors, including diabetes and hypertension (a target blood pressure of 130/80 mm Hg is appropriate for both conditions) in persons with coronary artery disease.

            Lifestyle Changes

Regular exercise reduces the frequency of anginal symptoms, increases functional capacity, and improves endothelial function.^24,33 Patients with chronic stable angina who are receiving medical therapy should exercise regularly, beginning at low levels for 20 to 30 minutes and increasing as symptoms allow. A recent randomized trial that compared the effects of daily exercise with those of angioplasty and stenting among patients with chronic stable angina and single-vessel coronary artery disease demonstrated better outcomes (in terms of major adverse events and improved exercise capacity) at one year in the exercise group than in the revascularization group.³⁴

Although dietary modification has not been studied specifically in patients with chronic stable angina, in a trial involving patients with a history of myocardial infarction who had been randomly assigned to follow either a Mediterranean diet or a prudent Western diet, the rate of cardiovascular events was 47 percent lower in the Mediterranean-diet group than in the Western-diet group, and this difference persisted for four years.³⁵ Trials involving multifactorial risk modification, including exercise, a low-fat diet, and smoking cessation, have demonstrated improvements in the progression of angina and coronary disease.³⁶

Vigorous efforts at smoking cessation and weight control are mandatory in patients with chronic stable angina. For patients with diabetes, a multifactorial approach that includes lifestyle changes and medications for glycemic control and coronary risk factors substantially reduces the risk of cardiovascular events.³⁷

            Pharmacologic Therapy

The use of aspirin at a dose of 81 to 150 mg per day reduces cardiovascular morbidity and mortality by 20 to 25 percent among patients with coronary artery disease. The results of several large, randomized trials indicate that the use of statins reduces the rate of coronary events and mortality in patients with established coronary artery disease and hyperlipidemia by 25 to 35 percent. Furthermore, a 25 to 30 percent reduction in revascularization rates in the large statin trials suggests a decrease in angina during the trials.³⁸ A recent trial involving patients with stable coronary artery disease demonstrated that treatment with 80 mg of atorvastatin daily slowed the progression of coronary atherosclerosis, as measured by intravascular ultrasound, over a period of 18 months, as compared with treatment with 40 mg of pravastatin daily.¹⁹ In another trial (the PROVE-IT–TIMI 22 [Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 study), the reduction of low-density lipoprotein (LDL) cholesterol levels to a mean of 62 mg per deciliter (1.6 mmol per liter) decreased the number of clinical events further than did a lesser reduction (to 95 mg per deciliter [2.5 mmol per liter]) in subjects with acute coronary ischemia.²⁰ A recent trial likewise showed a significantly lower rate of cardiovascular events among patients with stable coronary disease who were treated with 80 mg of atorvastatin daily (achieved mean LDL cholesterol, 77 mg per deciliter [2.0 mmol per liter]) than among those treated with 10 mg daily; persistent elevations in aminotransferase levels complicated therapy in 1.2 percent of patients in the high-dose group, as compared with 0.2 percent of those in the low-dose group.³⁹ The Adult Treatment Panel III of the National Cholesterol Education Program recently recommended target LDL cholesterol levels of 60 to 70 mg per deciliter (1.6 to 1.8 mmol per liter) in high-risk patients with coronary artery disease.⁴⁰

Statins reduce the levels of C-reactive protein, and two recent studies suggest that lowering these levels is as important as decreasing LDL cholesterol levels for the optimal reduction of coronary events.^41,42 Angiotensin-converting–enzyme (ACE) inhibitors have been reported to reduce morbidity and mortality among patients with coronary disease,^21,43 although the recent PEACE Trial (Prevention of Events with Angiotensin Converting Enzyme Inhibition Trial) did not confirm these findings,⁴⁴ possibly owing to the relatively low risk among patients in this trial as compared with those in the HOPE trial (Heart Outcomes Prevention Evaluation study) and the EUROPA study (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease).^21,43 ACE inhibitors should be prescribed for patients with chronic stable angina who have a history of myocardial infarction, hypertension, left ventricular systolic dysfunction, or diabetes, as well as for patients with impaired renal function who do not have a contraindication to the use of these agents.

Revascularization

Revascularization includes either percutaneous coronary intervention (i.e., balloon angioplasty and stenting) or coronary-artery bypass surgery. More than 1 million percutaneous coronary interventions were performed in the United States in 2003, far surpassing the number of surgical revascularizations. More than 80 percent of percutaneous interventions in the United States in 2004 were performed with the use of drug-eluting stents coated with sirolimus or paclitaxel.

Revascularization (performed by any technique) has not been shown to decrease the risk of myocardial infarction or death from coronary artery disease in patients with chronic stable angina and preserved left ventricular function. However, revascularization should be considered for persons with lifestyle-limiting angina who have a good medical regimen or for those with high-risk factors, such as symptomatic multivessel disease, proximal left anterior descending or left main artery disease, left ventricular systolic dysfunction, diabetes, a large ischemic burden ouclear or echocardiographic stress testing, early onset of ischemia on stress testing, or ST-segment depression of 2 mm or more.^24,45 Although coronary-artery bypass surgery achieves more complete and durable control of angina than percutaneous coronary intervention (with the use of noncoated stents), subsequent rates of myocardial infarction and death are similar over a five-year period with the two strategies.^46,47,48 Trials in which the use of noncoated stents were compared with balloon angioplasty have not shown significant differences in the rate of major adverse events, including acute myocardial infarction and death.⁴⁹ The long-term effect of drug-eluting stents on outcomes in chronic stable angina is still under evaluation; current data indicate that there have been significant reductions in the rate of restenosis at 6 to 12 months with coated stents, as compared with noncoated stents, resulting in substantial decreases in recurrent angina and the need for revascularization of target lesions. It is not clear how the long-term outcomes compare with those of coronary-artery bypass grafting.⁵⁰ Decisions regarding strategies for revascularization should take into account patients’ preferences and local experience.^24,45,46,48

Cardioprotective Therapy versus Percutaneous Intervention

Marked regional variability in the use of revascularization procedures suggests excessive use in some geographic areas. Several trials have indicated that treatment with a combination of vasculoprotective agents, along with lifestyle changes — with the option to proceed to percutaneous revascularization if symptoms worsen — results in rates of myocardial infarction and death that are not significantly different from those associated with revascularization in patients with class I or II stable angina whose disease involves one or two vessels.^51,52,53

Areas of Uncertainty

Some patients who are not candidates for coronary revascularization continue to have severe or limiting angina; almost all have multivessel coronary artery disease and have previously undergone revascularization and have target vessels that are not suitable for the procedure (because they are distal, diffuse, or of small caliber). The optimal approach to management of these cases remains uncertain. One option is the use of enhanced external counterpulsation; results of a sham-controlled, randomized trial, as well as observational data, suggest that this form of therapy decreases the severity and frequency of angina,²⁴ although objective reductions in ischemia have been variable.^54,55 Another approach is transmyocardial laser revascularization, in which multiple laser channels are made directly into the myocardium.^24,56,57 Both procedures are approved by the Food and Drug Administration (FDA), although the mechanisms by which they relieve angina remain uncertain. The role of promising new agents, including trimetazidine⁵⁸ and ranolazine,⁵⁹ that alter myocardial metabolism is currently unclear with regard to the treatment of angina; neither drug has received FDA approval.

Summary and Conclusions

The diagnosis of chronic stable angina is made on the basis of anginal symptoms, a noninvasive stress test that is positive for myocardial ischemia, and documentation of coronary atherosclerosis on angiography. Antianginal drugs should be prescribed in effective doses, usually beginning with a beta-blocker; aspirin is mandatory. Management should routinely include lifestyle modifications, including smoking cessation, weight control, and regular exercise, and aggressive control of other cardiovascular risk factors. Drugs to slow the progression of atherosclerosis, including statins and, in many cases, ACE inhibitors, are also indicated. The target LDL cholesterol level in persons with chronic stable angina is below 100 mg per deciliter (2.6 mmol per liter); in high-risk patients, the level is 60 to 70 mg per deciliter. Angiography is generally indicated if symptoms continue despite treatment with antianginal medications or if high-risk features appear on stress testing. I would recommend this, along with the other interventions described above, in a case such as that described in the vignette. Revascularization should be considered for persons with class II and III symptoms, a high risk as determined by diagnostic tests, or angina that the patient finds unacceptable despite medical management.

Case Title: Cardiac Radionuclide Imaging: A High-Risk Scan in a Symptomatic Man Taking Sildenafil

 

Initial Presentation

 

Chief Complaint: The patient is a 59-year-old male with a history of “heartburn” after taking sildenafil.

History of Present Illness: He reports receiving a free trial of sildenafil and on several occasions, he reported “heartburn” before, during, and after sexual activity. He underwent a percutaneous coronary intervention (PCI) 10 years ago for exertional “heartburn”; no reports from this procedure were available. Since that time, he reports doing well, without any symptoms until starting to take sildenafil. The patient’s baseline electrocardiogram (ECG) was withiormal limits.

Onset: One month ago

Duration: One month

 

Past Medical History:

– Coronary artery disease (CAD) status/post PCI 10 years ago

– Hypertension

– Hypercholesterolemia

– Diabetes mellitus

Family History: Both parents died in their 80s from cancer. No family history of premature CAD exists.

Social/Occupational History: He smokes a pipe once a day; drinks three beers per week; works as a grocery clerk at the local market.

 

Physical Findings

Age: 59

Gender: Male

Race: Caucasian

Height: 70 inches

Weight: 204 lbs

Blood Pressure: 132/90 mm Hg

Pulse: 83 bpm

Respiration: 16 breaths/minute

General Appearance: Comfortable, alert, orientated

Skin: No rash

Head and Neck: No jugular venous distention, no carotid bruit, carotid pulses normal

Chest and Lungs: Clear to auscultation bilaterally

Cardiac Exam: Regular rate and rhythm, S₁, S₂, no murmur

Abdomen: Soft, nontender, nondistended, normal active bowel sounds

Extremities (pulse, edema, etc.): Radial and femoral pulses 2+ bilaterally, trace pedal edema

Neurologic: Grossly normal

 

Which of the following is an incorrect statement regarding sildenafil citrate (Viagra)?

 

A.   Sildenafil is a selective inhibitor of cyclic GMP-specific phosphodiesterase type 5.

B.   Sildenafil results in smooth muscle relaxation, vasodilatation, and enhanced penile erection.

C.   Sildenafil increases systolic and diastolic blood pressure.

D.   Nitrates are contraindicated within 24 hours of using sildenafil because of the potential for a precipitous fall in blood pressure.

E.    Sildenafil has no significant effect on heart rate.

F.    The peak blood pressure effects of sildenafil typically occur one hour after the dose.

 

Commentary

The correct answer is C.

More than 30 million men are estimated to have erectile dysfunction in the United States, with sildenafil being taken by the majority. Sildenafil produces a transient modest reduction in systolic (8-10 mm Hg) and diastolic (5-6 mm Hg) blood pressures, with peak effects approximately one hour after the dose, and returning to baseline values by four hours after the dose. No significant effects on heart rate have been observed. The hypotensive effects are neither age dependent nor dose related.

With organic nitrates, the drop in blood pressure is potentiated, at times dangerously, making it contraindicated to take nitrates within 24 hours of using sildenafil.

 

 

Lab/Diagnostic Tests

Exercise single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI): exercised 5:34 minutes on Bruce protocol (7.0 MET), stopping for chest pain “heartburn.” Rest standing heart rate and blood pressure: 80 bpm and 122/80 mm Hg. Maximum heart rate and blood pressure: 139 bpm (85% maximum predicted heart rate) and 90/54 mm Hg. Exercise ECG is shown (Figures 1, 2, 3, 4). SPECT MPI with Tc-99m tetrofosmin is shown in both color & grey scale (Figure 5).

             

Figure 1

Figure 2

 

Figure 3

Figure 4