The Rationale for Initiating Therapy with Fixed-Dose

Combinations in Hypertension Thomas D. Giles, M.D.

Tulane University School of Medicine

New Orleans, LA

Disclosure:

Grant support: Astra Zeneca, Amgen, Abbott, Novartis, The National Institutes of Health, Boehringer-Ingelheim, and Sankyo/Forest.

Consultant for Novartis, Pfizer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Sankyo/Forest.

This presentation is supported by Novartis Pharmaceuticals

Historical Lessons on the Risks of Historical Lessons on the Risks of Hypertension and the Benefits of TreatmentHypertension and the Benefits of Treatment

CH

D In

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ence

Rat

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ears

0

10

20

30

40

50

Placebo ActiveTreatment

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The Framingham Study The Vet. Adm. Study II

Ann Intern Med. 1961; 55:33–50. JAMA. 1970; 213:1143–1152.

Hypertension IncreasesMorbidity and Mortality

Treatment DecreasesMorbidity and Mortality

0

20

40

60

80

100

120

140

Men Women

NormotensionHypertension

• VA Cooperative Study– HCTZ 50 mg bid– reserpine 0.1 mg bid– hydralazine 25 mg tid

• HCTZ, hydralazine and reserpine were combined in a single tablet

• Ser-Ap-Es, Ser-A-Gen, Seralazide, Serpazide

Combination Therapy for Hypertension Is Combination Therapy for Hypertension Is Not NewNot New

HCTZ, hydrochlorothiazide.Materson BJ et al. Hypertension. 1990;15:348-360.

CV=cardiovascular.

Neal B et al. Lancet. 2000;356:1955–1964.

Current Antihypertensive Therapy Current Antihypertensive Therapy Reduces CV EventsReduces CV Events

Ave

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Major CV Events

20%–30%

Stroke

30%–40%

CV Death

30%–40%

–60

–40

–20

0

–100

–80

Can we do better?Can we do better?

CVmortality

risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

CV Mortality Risk Doubles WithCV Mortality Risk Doubles WithEach 20/10 mm Hg BP Increment*Each 20/10 mm Hg BP Increment*

*Individuals aged 40-69 years, starting at BP 115/75 mm Hg.CV, cardiovascular; DBP, diastolic blood pressure; SBP, systolic blood pressure.Lewington S et al. Lancet. 2002;360:1903-1913.Chobanian AV et al. JAMA. 2003;289:2560-2572.

BP Differences of 10 mmHg Are Associated BP Differences of 10 mmHg Are Associated With Up to a 40% Effect on With Up to a 40% Effect on

CV Risk CV Risk

• Meta-analysis of 61 prospective, observational studies

• 1 million adults

• 12.7 million person-years

Lewington S et al. Lancet. 2002;360:1903–1913.

10 mmHg decrease in mean SBP 40% reduction

in risk of stroke mortality

30% reduction in risk of IHD mortality

Importance of Lowering BPImportance of Lowering BP (Data from Multiple Clinical Trials Measuring the Impact of

Hypertensive Therapy on Cardiovascular Mortality)

Greater differences in BP reduction mean greater reductions in the risk of cardiovascular mortality.

BP, blood pressureStaessen JA et al. Hypertension Research. 2005;28:385-407.

MRC2

MIDAS/NICS/VHAS

UKPDS C vs A

NORDIL INSIGHTHOT L vs H

HOT M vs H MRC1

HEPEWPHE

STOP1ATMHPART2/SCAT

CAPPP

Syst-China

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Cardiovascular Mortality

–5 0 5 10 15 20 25Difference (reference treatment minus experimental treatment) in Systolic BP (mmHg)

actively controlled trials.

placebo-controlled studies or trials with an untreated control group.

Negative values indicate tighter BP control on reference treatment.

HOPE

SHEP

STOP2/ACEIs

STOP2/CCBs

Target BP (mm Hg)Number of antihypertensive agents

1Trial 2 3 4

AASK MAP <92

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

IDNT SBP <135/DBP <85

ALLHAT SBP <140/DBP <90

Multiple Antihypertensive Agents Multiple Antihypertensive Agents Are Needed to Achieve Target BPAre Needed to Achieve Target BP

DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661.Lewis EJ et al. N Engl J Med. 2001;345:851-860.Cushman WC et al. J Clin Hypertens. 2002;4:393-405.

JNC 7 Treatment Guidelines recommend JNC 7 Treatment Guidelines recommend considering initiating therapy with two drugs when considering initiating therapy with two drugs when

BP >20/10mmHg above goalBP >20/10mmHg above goal

• JNC7 recommends BP be reduced to < 140/90mmHg

– For patients with diabetes or CKD: < 130/80mmHg

• Consider initiating therapy with two drugs in patients whose BP is >20/10mmHg above goal (Stage 2 and Stage 1 patients at high risk)

– “thereby increasing the likelihood of achieving goal BP in a timely manner….Multi-drug combinations often produce greater BP reduction at lower doses of the component agents resulting in fewer side effects. The use of fixed dose combinations may be more convenient and simplify the treatment regimen….”

– More than 2/3 of patients will require two or more agents

Chobanian et al., JAMA 2003; 289:2560–72,

Initial Fixed-Dose Combination TherapyInitial Fixed-Dose Combination Therapy

ADVANTAGES (1)• 2 drugs needed for control of Stage 2 BP• Low (therapeutic) dose of 2 drugs

– more effective than higher dose of single drug– usually well tolerated– adverse effects can be reduced

• Simplified treatment regimen: better adherence and potential for improved outcomes

• Economic benefits– Fewer copayments– health care costs reduced– fewer office visits

Initial Fixed-Dose Combination TherapyInitial Fixed-Dose Combination Therapy

ADVANTAGES (2)• Many combinations of agents with complementary MOA

available, e.g.– RAS blocker/diuretic– RAS blocker/CCB

• Patient response to fixed dose combinations predictable– FDCs well studied and efficacy and tolerability data

available in package inserts and publications– Similar data not always available for “ad hoc” free

combinations

Initial Fixed-Dose Combination TherapyInitial Fixed-Dose Combination TherapyDISADVANTAGES

• BP may be controlled with 1 drug in some patients– However, majority of patients require 2 drugs

• Combination ‘too potent’ causing hypotension– Benefit risk profile for each combination should be assessed in appropriate patient

population– Individualize therapy

• Additive risk for dose independent adverse effects– However, mono components likely to be taken as part of a multi drug regimen – Balance against risk of dose dependent side effects with high dose monotherapy and

risk of inadequate BP control (stroke, heart failure and MI)

• If adverse effects– must discontinue both drugs:

• However components have well characterized safety profiles so causal components usually identified easily

– more office visits– more lab tests

Conclusions (1)Conclusions (1)• Controlling hypertension reduces CV outcomes

– Doubling of CV risk with BP increases of 20/10mmHg

– Relationship between BP and CV risk is continuous: lower is better

• Majority of patients require >2 drugs to achieve BP goal

• JNC 7 recommends initial combination therapy in patients > 20/10 mm Hg over goal BP

Conclusions (2)Conclusions (2)

• Multiple combinations have been well studied in patients with Stage 2 hypertension

• Patient response to fixed dose combinations is predictable

• Incremental efficacy with good tolerability achieved with combinations representative of several antihypertensive classes, not just thiazide combinations as referenced in JNC7

• Benefit/risk profile of these agents can be determined from clinical studies to support appropriate clinical use