Using drugs to prevent CVD in high-risk patients added 11/10/01

Patient Care® Archive  Oct. 15, 2001

 http://pc.pdr.net/pc/public.htm?path=content/journals/p/data/2001/1015/10a01cvd.html

The benefits of pharmaceutical treatment for the primary and secondary prevention of cardiovascular disease (CVD) are overwhelming, and recommendations for aggressively treating high-risk patients—regardless of symptom profile—are based on a multitude of large, well-designed clinical trials. Most primary care physicians, however, are still not prescribing as often or as intensively as needed to meet preventive goals.

Acebutolol (Sectral)
Amlodipine (Norvasc)
Aspirin
Atorvastatin (Lipitor)
Bucindolol*
Bisoprolol (Zebeta)
Carvedilol (Coreg)
Colesevelam (Welchol)
Digoxin (Lanoxicaps, Lanoxin)
Diltiazem
Enalapril (Vasotec)
Felodipine (Plendil)
Fenofibrate (Tricor)
Fluvastatin (Lescol)
Gemfibrozil (Lopid)
Hydrochlorothiazide
Indinavir (Crixivan)
Isradipine (DynaCirc, DynaCirc CR)
Lovastatin (Mevacor)
Metoprolol (Lopressor, Toprol XL)
Niacin
Nicardipine (Cardene, Cardene SR)
Nifedipine (Adalat, Procardia)
Pindolol (Visken)
Pravastatin (Pravachol)
Ritonavir (Norvir)
Saquinavir (Invirase, Fortovase)
Simvastatin (Zocor)
Spironolactone (Aldactone)
Verapamil

*Investigational agent.

A survey of physicians throughout the country revealed that more than 40% were unfamiliar with the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI).¹ These physicians were not likely to treat systolic BP (SBP) unless it was higher than 160 mm Hg. In addition, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, otherwise known as statins, are underused, possibly due to unfounded concerns about hepatotoxicity (see "Common misconceptions"). Physicians who do not identify patients at high risk of CVD and prescribe the appropriate medications to meet the new targets for BP and lipid levels may be passing up an opportunity to reduce CVD morbidity and mortality in their practice.

Common misconceptions
Myths about the targets and medications for cardiovascular disease (CVD) prevention continue to pervade medicine, despite evidence from numerous well-designed trials. The following statements are false.

Statins often cause liver abnormalities
Liver toxicity associated with statin use may occur but its prevalence has been greatly exaggerated; less than 2% of all patients taking statins will experience significant ALT level elevations. Manufacturers of statins continue to reduce the recommended frequency of ALT or liver function test monitoring, and no data support the perception that long-term adverse hepatic effects may occur. Temporary liver abnormalities may occur, but continuation of statin therapy is recommended unless the enzyme levels rise to more than 3 times the upper limit of normal or myositis or renal failure develops.

Systolic BP = age + 100
The belief that systolic blood pressure (SBP) must rise with age to maintain cerebral profusion is false. The SBP goal is always lower than 140 mm Hg, and BP modification in older patients should be based on individual circumstances—including quality of life—not on age.

Beta-blockers are contraindicated in congestive heart failure
Despite evidence of beta-blockers' ability to reduce morbidity and mortality by about 30%, myths about their negative cardiac effects persist. Their use is recommended by the Heart Failure Society of America for the treatment of heart failure in patients in New York Heart Association classes 1, 2, and 3 who are given standard therapy with a diuretic, an ACE inhibitor, and digoxin.¹

Patients with diabetes should not receive niacin
Niacin may aggravate serum glucose level control in patients with diabetes, but the Arterial Disease Multiple Intervention Trial (ADMIT) showed that patients with diabetes can safely be treated with niacin.² Patients with diabetes who were using niacin were able to maintain glycemic control. Diabetes can be treated with niacin with careful monitoring.

WHO IS AT HIGH RISK?
The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) recommends goals and treatment strategies according to LDL cholesterol (LDL-C) levels and 10-year risk (see Table 1).² The Framingham Risk Score is used to calculate 10-year risk, and patients without heart disease or other equivalents with a 10-year risk of 20% or greater also fit into the category of CHD risk equivalents.

Risk
category 10-y risk LDL-C goal (mg/dL) LDL-C level at which to consider drug therapy (mg/dL)

CHD or CHD risk equivalents >20% <100 >130 (100-129, drug optional)*

>2 risk factors <20% <130   10-y risk 10%-20%: >130;  10-y risk <10%: >160

<1 risk factor <10%† <160 >190 (160-189, drug optional)

Key: CHD, coronary heart disease, LDL-C, LDL cholesterol.

*Clinical judgment will determine whether to use drug therapy when LDL-C is >100 mg/dL; defer drug therapy; or use drugs that primarily modify triglycerides and HDL cholesterol in this risk category.

†Because 10-y risk in this category is <10%, assessment in people with <1 risk factor is not necessary.

Source: National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).

The American Heart Association's guides to primary and secondary prevention of CVD can also provide interventions based on particular risk, although many of their recommendations have been superceded by the NCEP's revised statements.* Major risk factors to consider include family history of premature coronary heart disease (CHD), age, gender, smoking status, high total cholesterol levels, low HDL cholesterol (HDL-C) levels, and hypertension.^2,3 Definitively assess risk using the risk calculator on the National Heart Lung and Blood Institute Web site at http://www.nhlbi.nih.gov/about/framingham/riskabs.htm .

*See Guide to Primary Prevention of Cardiovascular Diseases and Preventing Heart Attack and Death in Patients with Coronary Disease at americanheart.org (stale link Dec 2001) 

Patients whose 10-year risk of a coronary event is 20% or greater should be treated as aggressively as people who already have CVD (including coronary artery disease, peripheral vascular disease—as determined by an ankle-brachial index of less than 0.9—stroke, or cerebrovascular disease) regardless of symptom profile. Patients with diabetes fall into this high-risk category.^4,5

Low HDL-C levels may increase the risk of coronary events. Although evidence is insufficient to recommend specific targets, an HDL-C level of 60 mg/dL or higher is now considered protective, whereas an HDL-C level lower than 40 mg/dL is a CVD risk factor.² (The cutoff point of the previous guidelines was 35 mg/dL). NCEP also recommends a new (although secondary) target of non-HDL-C levels (30 points higher than LDL-C levels) in patients with triglyceride (TG) levels higher than 200 mg/dL.

WHY AND HOW TO LOWER LIPID LEVELS
Patients with CVD or multiple risk factors for CVD clearly benefit from lipid-lowering therapy. Data from the following trials provide hard clinical end points for the use of statins:

Statins are the drugs of choice for reducing LDL-C levels and the frequency and severity of MIs and strokes.

Maximizing statin use
None of the major guidelines recommends one statin over another; all statins are safe and effective. Formularies may dictate use of less potent statins, which are usually adequate if prescribed in dosages that are required to meet goals. For example, a patient with diabetes and an LDL-C level of 130 mg/dL can usually attain the target level of 100 mg/dL with any statin. If the same patient starts with an LDL-C level of 160 mg/dL, however, a more powerful statin is probably needed. Start with a dosage that is reasonable to achieve target levels, and titrate upward as needed.

Frequency of monitoring varies, but most patients achieve their targets within a couple of months with the proper treatment and dosage titration (see the algorithm "Progression of drug therapy in primary prevention of CVD"). If high LDL-C levels are refractory after 6 weeks of statin therapy, titrate the dosage upward.

The Treatment to New Targets (TNT) study and Heart Protection Study are determining whether lower LDL-C levels are desirable. More definitive practice recommendations may be possible at the conclusion of these studies.

Using combination therapy
Sometimes, lowering LDL-C levels requires the addition of a second drug—a resin, fibric acid derivative, or niacin—to the statin regimen. Resins, such as colesevelam, interfere with the reabsorption of bile acids in the intestine and produce an additive effect. Note, however, that adding a resin to statin therapy is inadvisable when TG levels are higher than 150 mg/dL. In that case, a fibric acid derivative, such as gemfibrozil or fenofibrate, may benefit TG and HDL-C levels. Augmenting statin therapy with niacin (titrating the dosage up to 3 g/d, if needed) may also raise low HDL-C levels, which are frequently associated with high TG levels, especially in patients with diabetes or abnormal glucose tolerance.

Adverse effects
Statins are generally well-tolerated and have an excellent safety profile, but some side effects may occur, especially when statins are used in conjunction with a fibrate or niacin. Although myositis and muscle aches and pains are the most common adverse effects of statins, fewer than 5% of patients will be affected. Symptoms of myositis can signal elevated creatine phosphokinase (CPK) levels, which may warrant immediate discontinuation of the drug.

The frequency of CPK measurement varies. When starting a patient on combination therapy, obtain a baseline level and check CPK levels again after about 8 weeks. If results are normal and the patient is asymptomatic, measure CPK levels in 6 months and then annually. The presence of muscle aches and pains signals the need for more frequent monitoring. Advise all patients taking a statin to contact you if they have severe muscle aches or a sense of diminished well-being.

Rarely, patients taking a statin may have abnormal liver function tests. Up to 3 times the normal level of the serum ALT is acceptable. If ALT levels rise higher, discontinue statin treatment; hepatic function usually returns to normal.

Flushing and pruritus are common side effects associated with niacin therapy. To minimize flushing, instruct patients to take a 325-mg aspirin tablet about 30 minutes before taking niacin (for patient information, see "Taking lipid-lowering drugs"). If the pruritus is intolerable, recommend an antihistamine. Monitor liver function, particularly when prescribing 3 g/d or more of sustained-release niacin. Acanthosis nigricans, a reversible drug-induced skin lesion appearing as darkening of the skin on different parts of the body, is a rare side effect of niacin.

Taking lipid-lowering drugs
Lowering high blood cholesterol levels is an important way to reduce your risk of heart disease. Three common types of medications are resins, statins, and niacin. These tips can help make it easier to remember to take your pills.

Remembering to take pills
Taking medication consistently is half the battle. You will get the most out of your pills when they are taken regularly.

The best way to take resins
Drugs that lower cholesterol levels, called resins, include colestipol and cholestyramine. If you are taking the tablet form, drink a large glass of water with each pill. If you are given the resin powder, mix the prescribed amount in a glass of juice, milk, or water—at least 2 to 6 oz of fluid per packet or scoop of resin powder. Your doctor will tell you how much resin to take. Generally, you will start with 1 packet per day and work up to 3 to 6 packets per day, depending on what works best for you.

Side effects may include constipation, bloating, gas, and heartburn. These problems usually subside as your body adjusts to the medication. To reduce constipation, increase your intake of fluid and dietary fiber. When drinking the resin mixture, try to avoid swallowing air, which can cause bloating or gas.

The best way to take statins
Side effects are rare with statins. You might have an upset stomach while your body adjusts to the new medication, but this usually resolves after a few days.

The best way to take niacin
Immediate-release niacin comes either as a tablet or capsule. It dissolves in the stomach within minutes.

If you have any questions or problems with any of your medications, call your doctor.

Drug interactions
Combining simvastatin or lovastatin with protease inhibitors, which inhibit the P-450-3A4 cytochrome system, can cause plasma levels to rise more than 30 to 35 times above normal. Such drugs include indinavir, saquinavir, and ritonavir.

Nonetheless, physicians are beginning to use statins in patients with HIV infection who are being treated with protease inhibitors, since these drugs cause lipid abnormalities. Pravastatin and fluvastatin are the safest statins to use in such circumstances, since they do not inhibit the P-450-3A4 cytochrome system. Atorvastatin, a minor 3A4 substrate, may also have no clinically significant interactions with protease inhibitors.

TARGETING SBP
SBP is the most critical factor for diagnosis and treatment of hypertension. Data from the Framingham study show that 91% of patients with hypertension who are middle-aged or older can be categorized and treated on the basis of SBP alone.³ As people age, diastolic BP tends to level off but SBP rises and pulse pressure widens.¹³ The BP target for the general population is lower than 140/90 mm Hg, independent of age, as long as therapy to achieve that level is tolerated.¹⁴ The target for secondary prevention is lower than 130/85 mm Hg, but a BP lower than 120/80 mm Hg is optimal.

Who needs antihypertensive medication?
Lifestyle modifications should be included in antihypertensive therapy regardless of medication use.* Antihypertensive medication is warranted, however, when patients have

*See "Nondrug approaches to hypertension," Patient Care, June 15, 2001; also available at http://www.patientcareonline.com .

Physicians can monitor patients with diabetes with spot urine checks for the albumin to creatinine ratio instead of with a 24-hour urine collection. A ratio of 30:300 signifies microalbuminuria.

Initiating and augmenting therapy
Some patients may require only one drug to maintain normal BP whereas others may require more (see the algorithm "Treating hypertension"). Diuretics and beta-blockers are the drugs of choice for uncomplicated hypertension, according to JNC-VI guidelines. However, ACE inhibitors are usually first-line therapy for patients in high-risk groups.

If high dosages of ACE inhibitors are not associated with sufficient BP reductions, add a low-dose diuretic based on the serum creatinine level. If this is 1.8 mg/dL or more, use a loop diuretic; if it is less than 1.8 mg/dL, use a thiazide. Consider adding a long-acting calcium channel blocker such as verapamil, diltiazem, amlodipine, felodipine, nicardipine, or isradipine to the ACE inhibitor/diuretic combination if necessary. For high-risk patients who are still not at goal, choose a fourth drug based on resting heart rate. If baseline heart rate is 84 beats per minute (bpm) or more, add a low-dose beta-blocker or alpha-beta-blocker combination. If heart rate is less than 84 bpm, add a different subclass of calcium channel blocker that has a different mechanism. A long-acting alpha-blocker taken nightly may also provide the additional control some patients need.

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) compares ACE inhibitors, calcium channel blockers, and diuretics head to head.¹⁵ The results of the trial will influence recommendations from JNC-VII, scheduled to be published by 2003. The trial should also reveal whether actual outcomes vary among different classes of antihypertensives. ACE inhibitors and angiotensin-receptor blockers, however, are already believed to have better outcomes than calcium channel blockers. When at least 3 drugs are necessary, consider an ACE inhibitor/beta-blocker/diuretic combination.

Special considerations for subgroups
A number of factors influence the selection of an antihypertensive drug regimen. Special concerns become a factor in various groups of patients.

Older patients Although beta-blockers are cardioprotective in patients with known CVD, this drug class does not confer as much protection on older patients who do not have coronary disease. JNC-VI suggests treating older patients who have isolated systolic hypertension with either a low-dose diuretic or a long-acting dihydropyridine calcium channel blocker such as amlodipine to increase the efficacy of beta-blockers and ACE inhibitors.¹⁶ Unless the patient has diabetes, try the diuretic first, and monitor potassium levels.

Patients with diabetes If a patient has diabetes and isolated systolic hypertension, start with an ACE inhibitor. Some experts believe that the addition of a diuretic and a calcium channel blocker can help preserve kidney function. Start with amlodipine, since it does not increase resting sympathetic tone. Maintaining glycemic control in patients with diabetes may have the added benefit of raising HDL-C levels.

Patients with CHF Using an intrinsic sympathomimetic activity beta-blocker that raises resting heart rate, such as pindolol or acebutolol, is contraindicated in post-MI patients. In addition, the Beta-Blocker Evaluation Survival Trial (BEST) showed that bucindolol, an investigational agent, did not reduce morbidity and mortality.¹⁷ The following beta-blockers have shown conclusive benefits in reducing morbidity and mortality in heart failure

Spironolactone can also reduce CVD risk—particularly in patients with class 3 and class 4 CHF—when added to digoxin, a diuretic, an ACE inhibitor, and a beta-blocker. The risk of hyperkalemia may increase when spironolactone is used in high doses (more than 25 mg) with an ACE inhibitor. Use caution if baseline potassium levels are greater than 5 mEq/L, or serum creatinine levels are greater than 2.5 mg/dL.

Race Recent data suggest that black patients may respond differently from white patients to cardioprotective medications. In a recent trial, enalapril significantly reduced SBP and hospitalization rates among white patients with left ventricular dysfunction but had no effect on matched black patients.¹⁸

Recommendations promote the use of thiazides over calcium channel blockers for initial treatment in black patients with hypertension. Yet, a study of nifedipine, verapamil, hydrochlorothiazide, and enalapril in 409 black South African men and women with hypertension had unexpected results.¹⁹ Investigators found that the BP control rate was 61% to 63% with the calcium channel blockers, 26% with the thiazide, and 3.4% with the ACE inhibitor.

Treating black patients may require titrating up to high dosages of an ACE inhibitor. If BP remains refractory, titrate up to the full dosage of the ACE inhibitor, add a diuretic, or switch to or add a calcium channel blocker.

ACE inhibitors may induce cough, which can necessitate discontinuation of these agents in about 10% of patients. Any antihypertensive drug can lower BP excessively and cause dizziness or lightheadedness. Beta-blockers can slow the pulse excessively or cause fatigue, intolerance of cold weather, and depression. They may be difficult to use in geriatric patients because bradycardia is common. Diuretics may make patients vulnerable to rhythm irregularities, low potassium levels, and weakness.

During office visits, check orthostatic BP of patients taking antihypertensive medication. Take BP while the patient is lying down, then when standing. If BP drops significantly after the patient stands up, reinforce the importance of getting up slowly. Advise patients to call you if symptoms of weakness or dizziness worsen.

PracticePoint

Boosting medication compliance
Patients with cardiovascular disease (CVD) or risk factors for it often take multiple medications. Here are some ways to help such patients understand the necessity of complicated drug regimens and foster compliance.

This PracticePoint was contributed by practice management consultant CATHY L. KLEIN, LPN, CPC, Independent Consultant Representative, Muncie, Ind. clklein@home.com

REFERENCES

C. WAYNE WEART, PharmD, Professor and Chairman of the Department of Pharmacy Practice, and Associate Professor of Family Medicine, Medical University of South Carolina Colleges of Pharmacy and Medicine, Charleston. He is a member of the Patient Care Subspecialist Advisory Board.