~Atherosclerosis (Coronary Artery Disease), Part 5 - Conventional Medical Therapy

CONVENTIONAL MEDICAL THERAPY
  • Drug Treatments
  • Invasive Procedures
Drug Treatments
  • Beta-Blockers
  • Calcium Channel-Blockers
  • Angiotensin-Converting Enzyme (ACE) Inhibitors
  • Angiotension II Receptor Blockers
  • Vasodilators
  • Cardiac Glycosides/Anti-Arrhythmics
  • Diuretics
  • Cholesterol-Lowering Drugs
  • Treating "Bad" Cholesterol with "Good" Cholesterol: A New Drug on the Horizon
This section includes examples of drugs used in the conventional treatment of CHD. The list provides examples of the various types of medications available. Surgical procedures will be briefly described. More comprehensive information may be found in Cardiovascular Disease: Comprehensive Analysis.

Beta-Blockers

Beta-blockers "block" the effects of adrenaline (and norepinephrine) on beta-receptors. This slows the nerve impulses that travel through the heart and the heart does not work as hard. This lessens the work output of the heart and less blood and oxygen are required for the heart to perform work. Typically, beta-blockers are prescribed to treat high blood pressure (hypertension), congestive heart failure (CHF), abnormal heart rhythms (arrhythmias), and chest pain (angina). Beta-blockers are sometimes used in heart attack patients to prevent future attacks.

Medications can alter the effects of beta-blockers. Physicians and pharmacists follow these interactions if they learn from the patient which medications are being used. While on beta-blockers, you should avoid caffeinated beverages (coffee, tea, and some soft drinks), over-the-counter cough and cold medicines, antihistamines, and antacids containing aluminum. Avoid alcohol because it decreases the efficacy of beta-blockers and inhibits methionine synthase, the most important enzyme in remethylating homocysteine to methionine. Common side effects associated with beta-blockers include drowsiness, fatigue, cold hands and feet, weakness or dizziness, and dry mouth, eyes, and skin. Less common side effects include difficulty breathing, bradycardia (slow heartbeat), and swelling of the hands and feet. Impotence, gastrointestinal disturbances, joint discomfort, and depression occur rarely (Texas Heart Institute 2003a).

According to physicians and pharmacists, even though beta-adrenergic blockers can significantly reduce mortality after a myocardial infarction, these agents are prescribed to only a minority of patients. Underutilization of beta-blockers may be attributed to fear of adverse effects, especially by the elderly, and in patients with disorders such as diabetes or heart failure. With careful dosing and monitoring, the benefits of beta-blockers after myocardial infarction far outweigh the potential risks in most patients (Howard et al. 2000). Commonly prescribed beta-adrenergic blockers drugs include: atenolol (Tenoretic®, Tenormin®), metoprolol (Lopressor®, Toprol XL®), nadolol (Corgard®), and propranolol (Inderal®).

Natural agents having beta-blocking activity include grape seed extract (procyanidins), green tea, hawthorn, magnesium, and the amino acid taurine.

Calcium Channel-Blockers

Calcium-channel blockers slow the rate at which calcium passes to the contractile fibers of heart muscle and into the vessel walls, a sequence that relaxes the vessels. Relaxed vessels allow the blood to flow more easily, thereby reducing blood pressure. In addition to treating hypertension, calcium channel blockers are used to treat chest pain (angina), and irregular heartbeats (arrhythmia).

Because various drugs (beta-blockers, ACE inhibitors, anti-arrhythmics, diuretics, some eye medications, and corticosteroids) and large doses of calcium and vitamin D may interact with calcium channel blockers, the prescribing physician should be aware of the individual's list of all drugs and supplements. Avoid smoking while taking calcium-channel blockers because it may cause rapid heartbeat (tachycardia).

Common side effects associated with calcium channel blockers are fatigue, flushing, swelling of the abdomen, ankles, or feet, and heartburn. Less common side effects are changes in heart rate, either tachycardia or bradycardia (slow heart rate), shortness of breath, difficulty swallowing, and dizziness, numbness in hands and feet, and gastrointestinal disturbances. Chest pains, jaundice, and fainting are rarely reported (Texas Heart Institute 2003b).

Calcium channel blockers are classified as short-, intermediate-, and long- acting. Most short-acting calcium channel blockers have been taken off the market, and replaced by the longer-acting ones that have not been associated with increased risk for heart disease (Estacio et al. 1998; Mirkin 2002).

Calcium channel blockers increase the risk of developing cancer (Pahor et al. 1996), perhaps through interference with apoptosis, or programmed cell death, a defense against cancer. Reports of cancer with calcium channel blocker usage are controversial (Kizer et al. 2001). The use of particular types of antihypertensive medications, including immediate-release calcium channel blockers, may modestly increase the risk of breast carcinoma among older women. Reports have demonstrated an increased risk of cancer among users of verapamil, but it is too early to conclude that calcium channel blockers are associated with cancer (Beiderbeck-Noll et al. 2003; Li et al. 2003).

Commonly prescribed calcium-channel blockers are diltiazem (Cardizem CD®, Cardizem SR®, Dilacor XR®), nifedipine (Procardia XL®), and verapamil (Calan®, Calan SR®, Isoptin®, Isoptin SR®, Verelan®).

Angelica, garlic, ginger, ginkgo biloba, grape seed, green tea (Camellia sinensis), hawthorn, magnesium, and olive leaf have some calcium-channel blocking activity.

Angiotensin-Converting Enzyme (ACE) Inhibitors

The juxtaglomerular cells in the kidneys stimulate renin secretion when either blood volume or serum sodium decreases. The enzyme renin participates in the conversion of angiotensinogen to angiotensin I, which is rapidly hydrolyzed to form the active compound angiotensin II. The vasoconstrictive action of angiotensin II decreases glomerular filtration rate while its action on aldosterone release (a mineralocorticoid hormone produced by the adrenal cortex) promotes sodium retention, causing fluid and sodium reabsorption. Drugs that inhibit the angiotensin-converting enzyme (ACE) decrease sodium and water retention, reduce blood pressure, improve cardiac output, and typically decrease heart size.

ACE inhibitors are used to treat congestive heart failure (CHF) and hypertension. Following a heart attack, patients are often prescribed ACE inhibitors to prevent further damage to the heart. ACE inhibitors are prescribed for kidney problems associated with diabetes.

The physician will evaluate all drug and supplement use before initiating ACE-inhibiting therapy, especially diuretics and supplements containing potassium. A common side effect is a dry cough, sometimes making speech difficult. Less common side effects include gastrointestinal disturbances, numbness or tingling in the hands and feet, joint pain, fever, lightheadedness, and fatigue. Jaundice and edema are reported rarely (Texas Heart Institute 2003c).

Some commonly prescribed ACE inhibitors are captopril (Capoten®), enalapril (Vasotec®), and lisinopril, (Prinivil®, Zestril®).

Angiotension II Receptor Blockers

Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II. There are definite benefits to selective blockade of angiotensin II receptors, which mediate the very potent vasoconstricting actions of angiotensin II on arterial vasculature. Any of the drugs described in this section (or for high blood pressure) are beneficial for those with atherosclerosis because they lower blood pressure. High blood pressure in combination with atherosclerosis is common, but high blood pressure predisposes arterial plaque to rupturing, causing strokes or heart attacks. Angiotensin II is the most powerful vasoconstricting hormone affecting the arterial vasculature. Because the diseased arterial wall cells are already compromised by atherosclerosis, it is dangerous to stimulate such compromised cells with a strong vasoconstricting hormone like angiotensin II without risking the rupture of the plaque lining those cells. For this reason, angiotensin II receptor blockers are the best drug choice. These drugs specifically block the arterial vascular cells from excessive constriction mediated by angiotensin II.

Losartan was the first marketed angiotensin II receptor antagonist. It shows no risk of angioedema or cough. The AT1 subtype of angiotensin II receptors, which losartan blocks, occurs in vascular and myocardial tissue. Losartan is available alone as CozaarR, or in combination with hydrochlorthiazide (a common diuretic) marketed as HyzaarR. Both drugs will lower blood pressure (Oates and Brown 2001).

Years ago the Life Extension Foundation recommended angiotensin II receptor blockers for first line therapy by naming the first drugs approved in this class: Cozaar® and Hyzaar®. There is now a new member to this class called Benicar® that shows once-daily dosing (Neutel et al. 2002). Benicar® is usually given at a dose of 20 mg with a possible dose increase to 40 mg after two weeks. The Life Extension Foundation recommends that Benicar® is the best blood pressure-lowering drug product available for use in the individual that has high blood pressure that is further complicated by atherosclerosis.

Vasodilators

Vasodilating drugs act on blood vessels, opening the vessel by relaxing the muscular walls. There are four types of drugs that influence vasodilation: (1) beta-blockers, (2) direct-acting vasodilators, (3) ACE inhibitors, and (4) calcium channel blockers.

Some beta-blockers have vasodilator properties, others do not. The drugs Coreg® and pindolol block beta-1 and beta-2 receptors and are classified as direct vasodilators (enlarging arteries and increasing blood flow). Coreg® has some alpha-blocking ability as well as antioxidant potential. Labetalol (Normodyne®), blocks alpha, beta-1 and beta-2 receptors, causing greater vasodilation. Vasodilating and non-vasodilating beta-blockers reduced total hospitalizations and hospitalizations due to CHF (Bonet et al. 2000).

Hydralazine, minoxidil (Rogaine®) and nitroglycerin (NTG) are direct vasodilators (NTG is frequently used for angina) (American Family Physician 1998). ACE inhibitors vasodilate by inhibiting the formation of the body's most powerful constricting hormone, angiotensin II. By blocking its formation, arteries can dilate and blood pressure is typically reduced. Calcium channel blockers relax the tone of vascular smooth muscles, which promotes dilation. Certain calcium channel blockers affect the heart more than blood vessels (i.e., diltiazem and verapamil), while others (nifedipine and nicardipine) have greater effects on blood vessels than on the heart. Some vitamins, minerals, and various herbs have vasodilating potential: angelica, garlic, ginger, ginkgo biloba, hawthorn, magnesium, niacin, and olive leaf.

Cardiac Glycosides/Anti-Arrhythmics

Cardiac glycosides are obtained from digitalis purpurea and digitalis lanata, other plants that contain steroid glycosides, or their semi-synthetic derivatives. Cardiac glycosides are commonly used for CHF because they increase the force of cardiac contraction without significantly affecting other cardiovascular parameters. Cardiac glycosides are toxic at larger doses. Cardiac glycosides include Digoxin®, digitoxin, Lanoxin®, Purgoxin®, and Crystodigin®.

Bugleweed (Lycopus virginicus) and taurine (a nonessential amino acid synthesized during the catabolism of homocysteine) have digitalis-like activity; however, never substitute a natural substance for a prescription drug without the supervision of a physician.

Diuretics

Diuretics reduce edema and lower blood pressure by reducing sodium and water retention. The three types of diuretics (thiazides, potassium-sparing diuretics, and high-loop diuretics) all work differently, but each reduces total body salt and water, and thus, reduces blood pressure. Thiazides are the most commonly used in hypertension. If thiazides fail to lower blood pressure, an additional diuretic may be prescribed.

CAUTION: Although the use of thiazide diuretics and potassium-sparing diuretics modestly increased risks of breast carcinoma and, the use of certain diuretics may increase the risk of breast carcinoma among older women (Li et al. 2003).

Angelica, bugleweed, curcumin, garlic, ginger, grape seed, green tea, hawthorn, olive leaf, taurine, vitamin B6, vitamin C, and vitamin E have diuretic properties.

Cholesterol-Lowering Drugs

When cholesterol levels remain high despite adequate dietary changes, weight loss, and regular exercise, or if other risk factors for cardiovascular disease exist, cholesterol-lowering drugs are often prescribed. (See the chapter entitled Drug Overdosing for a detailed discussion on this topic.)

The drugs most commonly used to lower LDL are the statin drugs: lovastatin (Mevacor®), pravastatin (Pravachol®), simvastatin (Zocor®), and atorvastatin (Lipitor®). Bile acid sequestrants are another class of drugs prescribed for reducing LDL levels: cholestyramine (LoCHOLEST®, Questran®) and colestipol (Colestid®). Typically, gemfibrozil (Lopid®), clofibrate (Atromid-S®), and probucol (Lorelco®) moderately reduce LDL levels (AHA 2004b).

Policosanol, gugulipid, niacin, artichoke extract, chromium, ginger, CLA, grapefruit pectin, curcumin, proanthocyanidins, soy protein, and tocotrienols have cholesterol-lowering effects. CoQ10 and garlic extract help to inhibit the oxidation of LDL.

Treating "Bad" Cholesterol with "Good" Cholesterol: A New Drug on the Horizon

ApoA-1 (Apolipoprotein A-1) is a protein component of HDL. ApoA-1 Milano is a rare genetic variant of ApoA-1 that was isolated in the blood of a family living in Italy. This genetic mutation has been found to promote an exceptionally healthy arterial system in spite of low levels of protective HDL and high levels of triglycerides. A middle-aged man with high triglyceride levels had very low levels of HDL, had no evidence of heart disease, but had the variant apolipoprotein A-1, that was subsequently named ApoA-1 Milano.

ApoA-1 Milano has an amino acid which has been replaced by the amino acid cysteine. Cysteine contains a sulfhydryl group. About 70% of ApoA-1 Milano comes in pairs, linked by the sulfhydryl groups. This restricts HDL size and growth, but allows the remaining 30% (of monomeric ApoA-1 Milano) to act as an antioxidant, protecting lipids from free radical oxidation. The monomeric form literally traps free radicals and prevents oxidization of healthy tissue and lipids lining arterial walls, preventing injury, and cholesterol deposits. Only the monomeric form protects lipids from oxidation. After over 20 years, despite unhealthy diets, ApoA-1 Milano carriers remain free of cardiovascular disease (Bieleicki et al. 2002). Less than 40 people have been identified as carriers of the Milano variant (Gualandri et al. 1985).

ETC-216 (developed by Esperion) is an investigational synthetic version of ApoA-1 Milano, which is combined with a phospholipid to form a complex that imitates the beneficial properties of HDL. ETC-216 might remove cholesterol deposits and prevent oxidation that causes cholesterol deposits (Bielicki et al. 2002). Studies demonstrated that ETC-216 rapidly removed plaque from diseased arteries. Phase II clinical trials are underway. The "ApoA-1 Milano Trial" enrolled 47 patients, 21 were given 15 mg/kg of ETC-216; 45 mg/kg of ETC-216 (15 patients); or placebo (11 patients) as weekly intravenous infusions for 5 weeks. ETC-216 was well tolerated (Nissen et al. 2003; Newton et al. 2002). Plaque volume decreased by 1.0% (3.2%) in the combined ETC-216 groups and slightly increased by 0.14% (3.1%) in the placebo group, with an absolute reduction in the combined treatment groups of 4.2% from baseline. It was concluded that five doses of intravenous ETC-216 at weekly intervals did produce significant regression of coronary atherosclerosis (Nissen et al. 2003). "We now know that it is possible to actively remove cholesterol plaques from the coronary arteries with drugs…eventually this approach will make a significant difference in the care of patients with CHD" (Nissen et al. 2003).

Combining a synthetic HDL with mechanisms similar to ApoA-1 Milano and conventional cholesterol-lowering therapies represents a new drug regimen to prevent lipid oxidation leading to cholesterol deposits and may cause regression of existing plaques (Bielicki et al. 2002).

Invasive Procedures
  • Coronary artery bypass
  • Angioplasty
  • Stenting
  • Intra-Coronary Radiation
  • Atherectomy
Coronary Artery Bypass

An estimated 200,000 Americans undergo coronary artery bypass grafting (CABG) surgery each year. Bypass surgery, once considered to be difficult or complicated, is now an almost routine surgical procedure in many medical centers. The procedure itself is relatively simple. A segment of healthy blood vessel, usually a chest artery (mammillary artery) or leg vein (saphenous vein), is grafted to bypass blocked segments of the coronary arteries. In appropriate persons, arm veins might be used because healing occurs faster in the arms than in the legs. Cedars-Sinai uses a chest artery instead of a leg vein in 95% of its cases, believing it improves long-term survival rates (Cedars-Sinai Heart Center 2003).

Usually after surgery (depending upon the individual's condition), 2-3 days are spent in an intensive care recovery unit with another few days required in the hospital. Costs also vary according to a patient's condition and geographic locale, but the average is $32,000 to $35,000. (See the Anesthesia and Surgical Precautions protocol to learn how to reduce surgical complications.)

Surgery is recommended for disabling angina uncontrolled by conventional therapy only in good surgical candidates. Disagreement remains for the indications for CABG. The Coronary Artery Surgery Study demonstrated that patients with healthy hearts but with one, two, or all three of the major coronary arteries blocked did surprisingly well, without surgery. Regardless of the number or severity of the blockages, each group had a low death rate of 1% a year (Anon. 1984; Graboys et al. 1987; Alderman et al. 1990; Murray 1999).

The severity of blockage does not determine blood flow in the artery. There is no correlation between blood flow and the severity of blockage. The majority of coronary arteries with a 96% blockage, had the most brisk blood flow while similar arteries, with only 40% blockage had severe flow restriction. The authors concluded that the blockages found on heart catheterization do not correlate with blood flow restriction (White et al. 1984; Winslow et al. 1988; Murray 1999).

The critical factor regarding whether a patient needs CABG or angioplasty is how well the left ventricular pump is working (not the degree of blockage or the number of arteries affected). Bypass is only helpful when the ejection fraction is less than 40%. 90% of bypass procedures are performed with ejection fractions greater than 50%, which is adequate for meeting circulatory needs. As many as 90% of all bypass procedures may be unnecessary (Murray 1999).

When CABG or angioplasty is necessary based on these accepted criteria, the procedures increase long-term survival and relieve symptoms for 85% of patients. The controversy as to when CABG is appropriate remains among the most respected of physicians.

CAUTION: Although CABG greatly improves how most patients feel, it does not cure heart disease. Unless preventive steps are taken, the processes that originally caused the disease will continue. Following CABG, it is important for patients to make prudent lifestyle changes.

Angioplasty

Angioplasty is used to widen arteries in the heart that are narrowed or blocked due to plaque formation. The technique used depends on where the blockage is, its shape, and whether the blockage is hard or soft plaque. Angioplasty offers a few advantages over coronary bypass surgery: (1) although invasive, it does not require use of a heart-lung machine; (2) it is performed under local anesthesia; and (3) it is not as costly as CABG. Ordinarily, only one or two days of hospitalization are required.

Percutaneous transluminal coronary angioplasty (PTCA; or balloon angioplasty) involves threading a catheter with an inflatable balloon-like tip through the arteries to the blocked area. The balloon is inflated, flattening the fatty deposits and widening the arterial channel, allowing more blood to reach the heart muscle.

Laser angioplasty uses a catheter with a laser tip rather than a balloon tip. The laser-tipped catheter is guided to the blockage and the laser tip is used to destroy the plaque. Each layer is vaporized into gaseous and liquid particles (AHA 2002a; HIP 2002). Lasers have been used with both angioplasty and bypass procedures but the risks have been high and the treatment is expensive.

Angioplasty can also be used in plaque-blocked arteries in the legs and the internal carotid artery, the major vessel carrying blood to the brain. But, angioplasty is not appropriate for all types of CHD and it is not effective in all individuals. Patients with diabetes mellitus have better survival odds with CABG compared to PTCA (Brooks et al. 2000). Diabetic patients do much worse in heart attacks and mortality when undergoing PTCA. In treated diabetics, the 7-year survival rate was 76% in the CABG group and 56% in the PTCA group. Among non-diabetics, the survival rates were 86% in the CABG group and 87% in the PTCA group.

Women have better success rates than men because the introduction of lower-profile stents has allowed their use in small and tortuous vessels, which are more predominant in women (Presbitero et al. 2003). Success rates have been estimated as high as 90% (Choicemedia 2001).

Standard angioplasty is associated with complications because the procedure traumatizes the vessel wall. Damaged cells try to heal and regenerate, forming scar tissue that re-clogs the artery (restenosis). Six to nine months after treatment, restenosis recurs in leg arteries (50-60%) and in the heart arteries (20-30%). The procedure is often repeated or surgery is performed instead (PCI 2002). The use of stents has improved the odds of a favorable outcome, providing the procedure is done in a hospital performing a high volume of angioplasty/stent procedures.

Balloon-induced arterial wall injury is the main cause of abrupt vessel closure and subsequent problems in PTCA. The most significant injury to the diseased wall occurs when high-pressure balloon inflations are employed (University of Edinburgh http://www.cpa.ed.ac.uk/news/research/17/6.html).

Restenosis research projects are evaluating the effects of various adjuncts to improve angioplasty outcome, including radiated stents, antibiotic-covered stents, stent products that release medications into the artery to prevent closure, and a new approach referred to as cryoplasty (PCI 2002).

During cryoplasty a tiny balloon is threaded into the clogged artery and filled with nitrous oxide. As pressurized liquid nitrous oxide is delivered into the balloon, it expands and turns into a gas, causing it to cool to sub-zero temperatures. The cooling prompts apoptosis (programmed cell death, presumably in the plaque cells), a natural occurrence that is gentler and less traumatic to the tissue than the compression of plaque against the tissue wall. The low temperature produces beneficial physiological changes in the cell wall. Because the treatment is gentler than standard angioplasty, it doesn't promote a "scarring" response, frequently evidenced in standard angioplasty (AHA 2002a; New Haven Register 2004; Wisconsin Heart and Vascular Clinic 2004). Like CABG, angioplasty does not cure atherosclerosis. Patients need to improve their lifestyle to improve influence cardiovascular outcomes.

Stenting

A coronary stent is a tube usually made from stainless steel mesh that comes in many sizes to match the size of coronary arteries. Often a stent is placed inside a coronary artery following angioplasty so that the artery will remain expanded. Once the artery has been widened by an angioplasty procedure, a stent catheter is threaded into the artery and placed around a deflated balloon. When the balloon is exactly positioned in the artery, it is inflated to expand the stent against the artery walls. Then the balloon catheter is removed, but the stent is left in place to hold the artery open (Columbia Weill Cornell Heart Institute 2003).

Intra-Coronary Radiation

In about a third of angioplasty patients, the expanded area of the artery narrows (restenosis) within six months. Cardiologists (Columbia Weill Cornell Heart Institute) have developed a technique called intra-coronary radiation, which uses radiation to prevent restenosis of an opened artery. In intra-coronary radiation, a balloon containing a solution of beta radiation is inserted into the expanded heart vessel. The heart vessel is irradiated for 10 minutes and the balloon is removed. Intra-coronary radiation has shown great promise in preventing artery restenosis (Columbia Weill Cornell Heart Institute 2003).

Atherectomy

In atherectomy, specialized devices are used to remove or cut away plaque, particularly blockages that are too hardened (calcified) for balloon angioplasty. Atherectomy procedures include extraction (a tiny rotating blade trims away plaque on the inside of artery walls); rotational (a high-speed, diamond-tipped drill penetrates fatty deposits, particularly hard, calcified deposits); and directional (a combination of a balloon and a shaving blade hone away deposits) (HIP 2002).

Chest pain is the most common complication of atherectomy, but other complications might include injury to the blood vessel lining, restenosis, blood clots, and bleeding at the site of insertion. More serious but less frequent complications are blood vessel holes, tears, or reduced blood flow to the heart. It is estimated that atherectomy is successful about 95% of the time; plaque reforms in 20-30% of patients (De Milto 2003).

Continued . . .


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