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Volume 16, No. 1Supplement 2January 2007

Supplement to

This publication is sponsored by Pfizer

A Single Tablet To HelpManage Patients WithHypertension and Other Cardiovascular Risk Factors

(AH) and a lipid-lowering (LL) therapy within a 91-dayperiod as an addition to their existing prescription medica-tion, the more medications patients took, the less likely theywere to refill their newly prescribed antihypertensive andlipid-lowering medications adequately.5 In this managedcare population study, patients were considered adherent toAH and LL therapy if they had sufficient AH and LL thera-pies to cover at least 80 percent of days per 91-day period;however, whether patients actually took the medication wasnot determined.*

In the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA), which involved 10,305treated hypertensive patients with additional risk factors andwithout CHD, Lipitor® (atorvastatin calcium) reduced the rel-ative risk of nonfatal myocardial infarction (MI) by 45 per-cent (P=.0002) and stroke by 26 percent (P=.033). Althoughthe reduction of fatal and nonfatal stroke did not reach a pre-defined significance level (P=.01), a favorable trend wasobserved. Relative risk reduction in the primary end point, acomposite of time to first occurrence of nonfatal MI or fatalCHD, was 36 percent (P=.0005). Patients in each treatment

Hypertension, an independent risk factor for coronaryheart disease (CHD), is highly prevalent in the UnitedStates.1 The most recent data from the National Health

and Nutrition Examination Survey (NHANES)2 indicate thatat least 61 million U.S. adults — 29 percent — had high bloodpressure (systolic ≥140 mm Hg or diastolic ≥90 mm Hg) in1999–2002.2

Hypertension is among the well-known modifiable riskfactors for CHD, along with other risk factors such as dys-lipidemia, smoking, obesity, and physical inactivity.3 Themajority of hypertensive patients have dyslipidemia as anadditional risk factor, according to NHANES 1999–2002.2

The Multiple Risk Factor Intervention Trial (MRFIT), inwhich middle-aged white men without CHD were followedfor a mean of 12 years, showed that in nonsmoking patientswith hypertension (n=202,619), the risk of a CHD deathincreases as cholesterol levels increase (Figure).4 Furthermore,the joint effect of hypertension and dyslipidemia on CHDmortality rates is greater than that of either risk factor alone.4

This makes managing blood pressure (BP) and dyslipid-emia even more important, in terms of CHD events.

Results of a large retrospective cohort study of patientswith hypertension in a managed care population showed thatamong patients who initially were given an antihypertensive

Managing Patients With Hypertension And Other Cardiovascular Risk Factors

FIGURE In hypertensive patients, risk of CV event increases as cholesterol levels increase

An examination of data from patientsscreened for the Multiple Risk Factor Inter-vention Trial (MRFIT), a primary preventiontrial studying the combined influence ofBP, serum cholesterol level, and smokingon age-adjusted CHD mortality in 316,099white men aged 35 to 57 years. This figuredepicts data on the correlation of CHDmortality to varying levels of BP and cholesterol in 202,619 nonsmoking white subjects followed up for an average of 12 years.

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*These data did not include Caduet® (amlodipine besylate/atorvastatin calcium). Noconclusion about Caduet, Norvasc® (amlodipine besylate), or Lipitor® (atorvastatincalcium) can be made about these data.

group had similar mean BP throughout the trial (finalmean BP of 138/80 mm Hg). All patients had three ormore additional risk factors, such as age, smoking, lowHDL-C, or family history of CHD.6

In the Collaborative Atorvastatin Diabetes Study(CARDS), which involved nearly 3,000 patients,Lipitor significantly reduced the relative risk of MI by42 percent (P=.007) and stroke by 48 percent (P=.016)in patients with type 2 diabetes and one or more addi-tional risk factor — including retinopathy, albumin-uria, hypertension, or current smoking — and with-out CHD.7

The Norvasc® (amlodipine besylate) component ofCaduet® (amlodipine besylate/atorvastatin calcium)was associated with significant incremental systolicblood pressure (SBP) reductions when added to exist-ing antihypertensive regimens. When added to 1, 2, or>3 antihypertensive agents, incremental BP reduc-tions were –17.6/10.1 mm Hg (n=321), –16.7/9.6 mmHg (n=276), –15.7/9.3 mm Hg (n=157), respectively.8

In patients with diabetes (n=309), reductions in BP inthose taking Norvasc plus 1, 2, or >3 antihypertensivemedications were –14.2/5.8 mm Hg, –15.1/9.4 mmHg, and –15.6/8.7 mm Hg, respectively.8 During the 1-year follow-up of this analysis, the median dose ofNorvasc was 5 mg.8

Norvasc significantly reduced BP across a broadrange of patients. In patients with mild-to-moderatehypertension (n=5,113), black patients (n=74), olderpatients (n=497), and patients with diabetes (n=240),BP reductions were –17.5/12.3 mm Hg, –23.9/17.1 mmHg, –24.3/10.8 mm Hg, and –19.1/8.8 mm Hg, respec-tively. The magnitude of BP reduction with Norvasc iscorrelated with the height of pretreatment elevation.9

For patients who are appropriate candidates for anti-hypertensive therapy with amlodipine besylate, a calciumchannel blocker, and LL therapy with atorvastatin calcium,Caduet combines these drugs in a single pill taken oncedaily.10 To facilitate individualized dosing, Caduet is availablein 11 dose combinations. These range from amlodipine 2.5 mg/atorvastatin 10 mg up to amlodipine 10 mg/atorvastatin 80 mg. Small, fragile, or elderly patients may bestarted on 2.5 mg/10 mg, 2.5 mg/20 mg, or 2.5 mg/40 mg.Dosage of Caduet should be individualized on the basis ofeffectiveness and tolerance for each individual componentand on the existing treatment regimen.

In a double-blind, placebo-controlled study, patients(N=1,660) with hypertension and dyslipidemia receivedonce-daily treatment with eight dose combinations ofamlodipine besylate and atorvastatin calcium, amlodipinebesylate alone, atorvastatin calcium alone, or placebo. At 8weeks, all eight combination-treatment groups ofamlodipine besylate and atorvastatin calcium demonstrateddose-related reductions in SBP, diastolic blood pressure(DBP), and LDL-C compared with placebo, with no overall

modification of effect of either component on SBP, DBP, andLDL-C.10

In clinical trials enrolling patients with comorbid hyper-tension and dyslipidemia, these agents have been generallywell tolerated. Caduet adverse experiences are similar innature, severity, and frequency to those reported previouslywith Norvasc and Lipitor taken separately.

Used with diet and exercise, Caduet is a single, once-dailytablet for hypertensive patients with additional CV risk fac-tors without CHD who need the blood pressure lowering ofamlodipine and the cardiovascular benefits of atorvastatin.With this single pill formulation, Caduet may simplifypatients’ medication regimen by reducing the number ofprescriptions to refill, and eliminating one copayment,† whiletreating two CV risk factors.

Important Safety Information

Caduet is a combination of two medications, Norvasc®

(amlodipine besylate) and Lipitor® (atorvastatin), and is

Managing Patients With Hypertension: Is Lowering Blood Pressure Enough?Managed care analysis by Steven Peskin, MD

Corporate Medical Director, MediMedia USA

Compelling data from landmark clinical trials, such as theMultiple Risk Factor Intervention Trial (MRFIT), demonstrate thepresence of hypertension, as well as additional cardiovascularrisk factors, including hypercholesterolemia, increases the risk ofCVD in patients with hypertension.

For physicians and other clinical executives responsible forpopulation health management, the message is clear. Interven-tions — lifestyle, behavioral, or pharma-cologic — that address more than one riskfactor may lead to greater risk reduction inthe cardiovascular morbidity and mortalityof hypertensive patients.

Simplifying medication regimens — forexample, by reducing pill count — mayresult in improved adherence.

This clinical brief summarizes importantkey clinical data on the blood-pressurelowering efficacy of Norvasc and cardiovascular benefits of Lipi-tor, the two components of Caduet that help support the ration-ale of Caduet treatment, which through Lipitor, helps to reduceCV risk in patients with hypertension without CHD and addi-tional risk factors, including dyslipidemia.

Steven Peskin, MD, is the medical director for MediMedia USA. He is anassistant clinical professor of medicine at the University of Medicineand Dentistry of New Jersey. Peskin is a former vice president andmedical director for Cigna and PacifiCare.

Steven Peskin, MD

Please see brief summary of prescribing information.

†Compared to amlodipine and atorvastatin administered separately.

indicated in patients for whom treatment with both Norvascand Lipitor is appropriate. Norvasc is indicated for the treat-ment of hypertension and chronic stable or vasospasticangina. Lipitor is indicated as an adjunct to diet and exerciseto reduce the risk of MI, revascularization procedures, andangina in adult patients with multiple risk factors but with-out clinically evident CHD; and to reduce elevated total-C,LDL-C, apo B, TG levels; and to increase HDL-C in patientswith primary hypercholesterolemia (heterozygous familialand nonfamilial) and mixed dyslipidemia.

Caduet is contraindicated in patients with active liver disease or unexplained persistent elevations of serum trans-aminases; in women who are pregnant or may become pregnant and/or nurse; in patients with hypersensitivity toany component of this medication.

Rare cases of rhabdomyolysis have been reported withthe Lipitor component of Caduet and with other statins.With any statin, tell patients to promptly report muscle pain,tenderness, or weakness. Discontinue drug if myopathy issuspected, if creatine phosphokinase (CPK) levels risemarkedly, or if the patient has risk factors for rhabdo-myolysis.

Due to increased risk of myopathy seen with the Lipitorcomponent of Caduet and other statins, physicians shouldcarefully consider combined therapy with fibric acid deriv-atives, erythromycin, immunosuppressive drugs, azole anti-fungals, or niacin and carefully monitor patients for signs orsymptoms of myopathy early during therapy and when titrat-ing dose of either drug.

It is recommended that liver function tests be performedprior to and 12 weeks following the initiation of Caduettherapy and any elevation in dose of the Lipitor compo-nent, and periodically thereafter. If ALT or AST values >3XULN persist, dose reduction or withdrawal of Lipitor isrecommended.

Generally CCBs should be used with caution in patientswith heart failure. In studies with Norvasc, there has been noevidence of worsened heart failure.

In a controlled clinical trial, the most common adverseevents were edema, headache, and dizziness. These were sim-ilar to those reported previously with Norvasc and/or Lipitor.

Please see brief summary of prescribing information.

References1. Chobanian AV, Bakris GL, Black HR, et al, and the National Blood

Pressure Education Program Coordinating Committee. The SeventhReport of the Joint National Committee on Detection, Evaluationand Treatment of High Blood Pressure: the JNC7 Report. JAMA.2003;289:2560–2572.

2. NHANES 1999–2002; morning examination subset (n=2,655); 2004U.S. Census projection of adults 20+ years.

3. National High Blood Pressure Education Program. The Seventh Reportof the Joint National Committee on Prevention, Detection, Evalua-tion, and Treatment of High Blood Pressure. National Institutes ofHealth, NIH Publication No. 04-5230. Aug. 2004.

4. Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarettesmoking, and death from coronary heart disease: overall findingsand differences by age for 316,099 white men. Multiple Risk FactorIntervention Trial Research Group. Arch Intern Med. 1992;152:56–64.

5. Chapman RH, Benner JS, Petrilla AA, et al. Predictors of adherencewith antihypertensive and lipid-lowering therapy. Arch Intern Med.2005;165:1147–1152.

6. Sever PS, Dahlöf B, Poulter NR, et al., for the ASCOT investigators.Prevention of coronary and stroke events with atorvastatin in hyper-tensive patients who have average or lower than average cholesterolconcentrations, in the Anglo-Scandinavian Cardiac OutcomesTrial–Lipid Lowering Arm (ASCOT-LLA): a multicentre ran-domised controlled trial. Lancet. 2003;361:1149–1158.

7. Colhoun HM, Betteridge DJ, Durrington PN, et al. on behalf of theCARDS investigators. Primary prevention of cardiovascular diseasewith atorvastatin in type 2 diabetes in the Collaborative AtorvastatinDiabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–696.

8. Bisognano J, McLaughlin T, Roberts CS, et al. Incremental effectivenessof amlodipine besylate in the treatment of hypertension with singleand multiple medication regimens. Am J Hypertens. 2004;17:676–683.

9. Levine CB, Fahrbach KR, Frame D, et al. Effect of amlodipine on sys-tolic blood pressure. Clin Ther. 2003;25:35–57.

10. Caduet [atorvastatin/amlodipine] prescribing information. New York:Pfizer Inc. April 2006.

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