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The Rationale for Initiating Therapy with Fixed-Dose Combinations in Hypertension. Thomas D. Giles, M.D. Tulane University School of Medicine New Orleans, LA.

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the rationale for initiating therapy with fixed dose combinations in hypertension

The Rationale for Initiating Therapy with Fixed-Dose Combinations in Hypertension

Thomas D. Giles, M.D.

Tulane University School of Medicine

New Orleans, LA

slide2

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 hypertension and the benefits of treatment
Historical Lessons on the Risks of Hypertension and the Benefits of Treatment

Hypertension IncreasesMorbidity and Mortality

Treatment DecreasesMorbidity and Mortality

CHD Incidence Rate/1000 Person Years

Cumulative Fatal & Nonfatal Endpoints

The Framingham Study

The Vet. Adm. Study II

Ann Intern Med. 1961; 55:33–50.

JAMA. 1970; 213:1143–1152.

slide4

Combination Therapy for Hypertension Is Not New

  • 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

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

current antihypertensive therapy reduces cv events

Can we do better?

Current Antihypertensive Therapy Reduces CV Events

Stroke

CV Death

Major CV

Events

0

–20

20%–30%

–40

30%–40%

30%–40%

Average Reduction in Events, %

–60

–80

–100

CV=cardiovascular.

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

slide6

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

8

7

6

5

CVmortalityrisk

4

3

2

1

0

115/75

135/85

155/95

175/105

SBP/DBP (mm Hg)

*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.

slide7

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

  • Meta-analysis of 61 prospective, observational studies
  • 1 million adults
  • 12.7 million person-years

30% reduction in risk of IHD mortality

10 mmHg decrease in mean SBP

40% reduction in risk of stroke mortality

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

slide8
Importance of Lowering BP(Data from Multiple Clinical Trials Measuring the Impact of Hypertensive Therapy on Cardiovascular Mortality)

Cardiovascular Mortality

actively controlled trials.

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

Negative values indicate tighter BP control on reference treatment.

1.50

MIDAS/NICS/VHAS

P=0.002

UKPDS C vs A

1.25

NORDIL

INSIGHT

HOT L vs H

STOP2/ACEIs

HOT M vs H

MRC1

1.00

MRC2

STOP2/CCBs

Odds Ratio (experimental/reference)

SHEP

HEP

0.75

STONE

Syst-Eur

EWPHE

CAPPP

HOPE

UKPDS L vs H

RCT70-80

Syst-China

0.50

PART2/SCAT

STOP1

ATMH

0.25

–5

0

5

10

15

20

25

Difference (reference treatment minus experimental treatment) in Systolic BP (mmHg)

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

BP, blood pressure

Staessen JA et al. Hypertension Research. 2005;28:385-407.

slide9

UKPDS DBP <85

ABCD DBP <75

MDRD MAP <92

HOT DBP <80

AASK MAP <92

IDNT SBP <135/DBP <85

ALLHAT SBP <140/DBP <90

Multiple Antihypertensive Agents Are Needed to Achieve Target BP

Number of antihypertensive agents

Trial

Target BP (mm Hg)

1

2

3

4

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.

slide10
JNC 7 Treatment Guidelines recommend considering initiating therapy with two drugs when BP >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 therapy
Initial 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 therapy12
Initial 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 therapy13
Initial Fixed-Dose Combination Therapy

DISADVANTAGES

  • 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