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A guide to recently approved cardiovascular medicationsCYNTHIA CHENG, MD, PhD, Department of Family Medicine, Jefferson Medical College, Thomas Jefferson University Hospital, Philadelphia, Pa.Among the latest arrivals are an antiarrhythmic, an antihypertensive, and 2 agents for dyslipidemia. What can these drugs offer your patients that was unavailable before?
With cardiovascular disease (CVD) still the leading cause of death in the United States, a major focus of medical research continues to be the development of more effective treatments. The past few years have ushered in a number of newly approved cardiovascular medications, and this review provides primary care clinicians with evidence-based recommendations and guidelines for using these drugs: • Dofetilide, an antiarrhythmic drug for atrial fibrillation/flutter • Eplerenone, an antihypertensive • Ezetimibe, an antihyperlipidemic agent • Rosuvastatin, a new statin for hyperlipidemia.
DofetilideTherapeutic role in primary care Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 2.3% of all adults in the United States and 5.9% of adults older than 65. It accounts for 5% of all hospital admissions. While many primary care clinicians may not initiate treatment with dofetilide, most are likely to see patients who are taking it, making it important for them to have a working knowledge of this medication. Indication Dofetilide, a class III antiarrhythmic agent, is effective in converting AF and atrial flutter to normal sinus rhythm (30% success rate) and in maintaining normal sinus rhythm (60%-70% success rate). Mechanism of action Class III antiarrhythmic agents are essentially potassium channel blockers; they make cardiac cells less likely to depolarize in response to electrical stimuli. Dosing When the drug is started for conversion to sinus rhythm, IV dosing is based on renal function and on the pharmacologic effect on the QT interval. Before patients can begin treatment with dofetilide for conversion of AF to normal sinus rhythm, all other antiarrhythmic agents must be withdrawn for a minimum of 3 plasma half-lives. In addition, patients must be hospitalized for a minimum of 3 days whenever the drug is either started or restarted. This measure has been shown to decrease the incidence of the dose-related risk of ventricular arrhythmia (torsade de pointes). Most patients with atrial flutter or AF who convert will do so within 24 to 36 hours after starting the medication. Restoration of sinus rhythm is more likely with recent-onset arrhythmia versus chronic persistent arrhythmia and with atrial flutter rather than with AF. Electrical conversion should be considered for patients who do not convert to normal sinus rhythm within 24 to 36 hours of initiation of therapy. For oral maintenance dosing, dofetilide is available in 125-, 250-, and 500-mcg capsules. Renal function and the QTc interval should be monitored every 3 months for patients on chronic therapy. Precautions Pregnancy category C. Contraindications Creatinine clearance of less than 20 mL/min; concomitant use of verapamil, hydrochlorothiazide, cimetidine, ketoconazole, and trimethoprim/sulfamethoxazole. Adverse reactions As with other class III antiarrhythmics, the most significant, potentially fatal side effect is torsade de pointes. This effect is dose-related, occurs most commonly in the first 3 days of therapy, and is more likely in the presence of renal dysfunction. In the Danish Investigations of Arrhythmia and Mortality on Dofetilide-CHF (DIAMOND-CHF) study, torsade also occurred more frequently in women and patients with congestive heart failure (CHF).1 Advantages Both dofetilide and amiodarone, another class III antiarrhythmic agent, have neutral effects on survival in post-MI patients. This is an advantage over other antiarrhythmic agents, such as flecainide, encainide, and moricizine (class 1C agents), and sotalol (another class III agent), which all increased mortality when compared with placebo. Compared with the other class III agents, dofetilide is devoid of noncardiac organ toxicities, such as those found with amiodarone, and negative inotropic effects, such as those occurring with sotalol. Disadvantages The need to hospitalize patients as a precaution when dofetilide is initiated may be viewed as an inconvenience. Note that this restriction was carried forward from the clinical studies of dofetilide, all of which used in-hospital drug administration. Summary Dofetilide may cause potentially fatal torsade de pointes in a small percentage of patients, but it may be particularly useful in those with both left ventricular dysfunction (LV) and AF, a patient population in which previous trials have shown increased mortality rates with other antiarrhythmics. Dofetilide appears to have less noncardiac toxicity and fewer adverse effects on heart rate and BP than the previously available class III agents, amiodarone and sotalol. Because of the small but serious potential for life-threatening torsade de pointes, dofetilide use should be reserved for patients with highly symptomatic AF or atrial flutter. Cost Average wholesale price (AWP) for a 30-day supply: $59.01.* *Source: 2003 Drug Topics Red Book. Montvale, NJ: Thomson PDR; 2003. EplerenoneTherapeutic role in primary care Eplerenone is the first selective aldosterone antagonist. It is currently approved by the FDA for 2 indications: hypertension and post-MI LV dysfunction. Mechanism of action Eplerenone selectively blocks the aldosterone receptor. In addition to the known sodium-retaining effect of aldosterone, which causes BP elevation, more recent studies have shown that aldosterone is associated with endothelial dysfunction and fibrotic effects in hypertension, CHF, and atherosclerosis. Dosing Eplerenone is available in 25-, 50-, and 100-mg formulations. The recommended starting dosage is 50 mg/d, which may be titrated to 200 mg/d. Initial BP-lowering effects occur within 2 weeks with maximal effects within 4 weeks. Precautions The following measures are advised with all known cytochrome P-450 3A4 inhibitors, including erythromycin, saquinavir, verapamil, and grapefruit juice, all of which can elevate blood levels of eplerenone: Patients should be counseled not to use salt substitutes containing potassium. Periodic monitoring for hyperkalemia is advised. In clinical trials, serum potassium levels were checked every 2 weeks for the first 1 to 2 months, then monthly thereafter. In addition, eplerenone is pregnancy category B. Contraindications Eplerenone is contraindicated in patients with hyperkalemia, those with type 2 diabetes with microalbuminuria (these patients have increased risk of hyperkalemia), persons with serum creatinine levels greater than 2.0/1.8 mg/dL, and those taking potent cytochrome P-450 3A4 inhibitors such as ketoconazole and itraconazole. Advantages Eplerenone has several advantages over its predecessor, the nonselective aldosterone antagonist, spironolactone. While spironolactone also works by blocking aldosterone action, it binds nonselectively to androgenic and progesterone receptors, leading to hormonal side effects (gynecomastia, irregular menstruation, and erectile dysfunction) that have limited its widespread use. Because eplerenone is more selective for the aldosterone receptor, it is associated with a reduced incidence of these adverse reactions (2% versus 7%-13%). A study comparing amlodipine and eplerenone showed equal BP-lowering effects but fewer side effects with eplerenone.2 Several studies have provided evidence of other potential roles for eplerenone. One trial showed that eplerenone reduces BP equally effectively in African American and Caucasian patients, as opposed to losartan, which was more effective in Caucasians.3 Another study demonstrated additive benefits with eplerenone when it was added to either an ACE inhibitor or an angiotensin-receptor blocker.4 Eplerenone also reduced LV mass and microalbuminuria similarly to enalapril.5 In patients with acute MI complicated by LV dysfunction and CHF, the addition of eplerenone to optimal medical therapy reduced morbidity and mortality when compared with placebo.6 In fact, eplerenone is the first aldosterone-receptor blocker to receive FDA approval specifically for LV dysfunction (ejection fraction of less than 40%) following MI, based on the results of the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS).6 Disadvantages The most common significant side effect of eplerenone (occurring in 2%-10% of patients in clinical trials) is hyperkalemia; other potential side effects (occurring in 2%-3% of patients) include headache, dizziness, diarrhea, and fatigue. More serious side effects including increased levels of gamma-glutamyl transferase and precipitation of angina/MI have also been noted (less than 1% of patients). Summary Eplerenone is a well-tolerated and effective antihypertensive agent with potential benefits beyond BP lowering. However, it is associated with a number of side effects, most commonly hyperkalemia. Cost AWP data are not yet available. (According to the manufacturer, pricing information will be released with availability of the drug early in 2004.) EzetimibeTherapeutic role in primary care Ezetimibe, the first in a new class of compounds, has an indication for lipid lowering as monotherapy or in combination therapy. While it is relatively weak as monotherapy (increases in HDL-cholesterol [HDL-C] levels of 1% and reductions in total cholesterol levels of 12%, LDL-cholesterol [LDL-C] levels of 18%, and triglyceride [TG] levels of 7%-9%), it works well in combination with other agents. For example, combining ezetimibe with a statin results in more LDL-C lowering than would occur by doubling the statin dose. One specific study in which ezetimibe was added to atorvastatin resulted in an additional 12% LDL-C reduction, 8% TG reduction, and 3% HDL-C increase.7 Ezetimibe also lowers levels of apolipoprotein B (Apo B), a lipid particle that has been identified as an independent predictor of coronary artery disease risk. Mechanism of action The unique mechanism of action of ezetimibe involves inhibition of cholesterol absorption from the small intestine. Dosing 10 mg/d. Precautions Pregnancy category C. Adverse reactions Reported at rates just slightly above placebo, adverse reactions of ezetimibe have been nonspecific and include fatigue, abdominal pain, diarrhea, pharyngitis/upper respiratory infection, arthralgias, myalgias, and back pain. In postmarketing experience, hypersensitivity reactions including angioedema and rash have also been reported. Advantages Ezetimibe is very well-tolerated with a side-effect profile nearly identical to that of placebo. Similarly, no significant drug interactions have been noted except when ezetimibe is administered concomitantly with cholestyramine, which reduces blood concentrations of ezetimibe by about 55%. Disadvantages Weak as monotherapy. Summary The main advantage of ezetimibe is its favorable safety profile. Because it is a relatively weak lipid-lowering agent as monotherapy, it should be used primarily in patients with mild dyslipidemia, or in conjunction with more powerful agents when monotherapy is inadequate to attain lipid goals. Cost AWP for a 30-day supply: $72.30.* *Source: 2003 Drug Topics Red Book. Montvale, NJ: Thomson PDR; 2003. RosuvastatinTherapeutic role in primary care This newly approved, 6th available statin that provides more lipid-lowering potency than other statin medications is indicated for the treatment of various hyperlipidemias. In a comparative trial with atorvastatin (the previously most potent statin), rosuvastatin provided an average of 8.4% greater lowering of LDL-C levels at any given dose, along with greater increases of HDL-C levels, although the highest atorvastatin dose (80 mg) did provide greater lowering of TG concentrations. In premarketing trials, rosuvastatin has lowered LDL-C levels by 45% to 63% and increased HDL-C levels by 8% to 14%. Like ezetimibe, rosuvastatin also lowers Apo B levels. Mechanism of action HMG-CoA reductase inhibitor. Dosing Rosuvastatin is available in 5-, 10-, 20-, or 40-mg strengths with a corresponding dosage range of 5 to 40 mg/d. The recommended starting dosage is 10 mg/d, although the manufacturer suggests considering starting at 20 mg/d for patients with marked hypercholesterolemia. The 40-mg/d dosage should be reserved for patients who fail to achieve goal LDL-C levels with the 20-mg/d dosage. Precautions Pregnancy category X. Contraindications These are similar to the contraindications for the other statins and include active liver disease and/or elevated liver function test results. Liver function should be monitored at baseline, at 12 weeks following initiation of therapy, and with dosage increases. For patients with severely impaired kidney function, rosuvastatin should be started at 5 mg/d and limited to a maximum dosage of 10 mg/d. Adverse reactions As with the other statins, dosage-related adverse reactions occur at a low rate and are usually mild and transient. Myalgia, constipation, asthenia, nausea, and abdominal pain were the most common side effects in clinical trials. Rare cases of rhabdomyolysis and acute renal failure associated with myoglobinuria have been reported with rosuvastatin and previous statins. Almost all the rare cases of rhabdomyolysis with rosuvastatin occurred at the 80-mg/d dosage, which was not approved by the FDA. Advantages As monotherapy, rosuvastatin provides greater LDL-C lowering benefits than any of the previously available statins. Disadvantages While the toxicity of rosuvastatin in premarketing trials has not exceeded that seen with previous statins, the lack of long-term safety data is a relative disadvantage. Also, although rosuvastatin would be expected to provide the same morbidity and mortality benefits of existing HMG-CoA reductase inhibitors, there are currently no studies establishing the effect of this new statin on morbidity and mortality. Summary More than 24,000 patients in the United States have received rosuvastatin in clinical trials to date, making this the largest clinical development program ever undertaken for a statin drug. However, the long-term safety of this newest and most potent statin remains to be established. Cost Retail price for a 30-day supply: $69.99.* *Source: http://www.drugstore.com .
PRODUCED BY PETER D'EPIRO
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