The Rationale for Initiating Therapy with FixedDose Combinations in Hypertension

1
The Rationale for Initiating Therapy with
Fixed-Dose Combinations in Hypertension

• Thomas D. Giles, M.D.
• Tulane University School of Medicine
• New Orleans, LA

2
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
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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 553350.
JAMA. 1970 21311431152.
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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. 199015348-360.
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Current Antihypertensive Therapy Reduces CV Events
Major CV Events
Stroke
CV Death
0
20
2030
40
3040
3040
Average Reduction in Events,
60
80
100
CVcardiovascular. Neal B et al. Lancet.
200035619551964.
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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.
20023601903-1913. Chobanian AV et al. JAMA.
20032892560-2572.
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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. 200236019031913.
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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
UKPDS C vs A
P0.002
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
EWPHE
Syst-Eur
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. 200528385-407.
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Multiple Antihypertensive Agents Are Needed to
Achieve Target BP
Number of antihypertensive agents
Target BP (mm Hg)
Trial
1
2
3
4
DBP, diastolic blood pressure MAP, mean arterial
pressure SBP, systolic blood pressure. Bakris
GL et al. Am J Kidney Dis. 200036646-661. Lewis
EJ et al. N Engl J Med. 2001345851-860. Cushman
WC et al. J Clin Hypertens. 20024393-405.
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JNC 7 Treatment Guidelines recommend considering
initiating therapy with two drugs when BP
gt20/10mmHg above goal

• JNC7 recommends BP be reduced to lt 140/90mmHg
• For patients with diabetes or CKD lt 130/80mmHg
• Consider initiating therapy with two drugs in
  patients whose BP is gt20/10mmHg 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 289256072,
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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

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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

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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

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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 gt2 drugs to achieve
  BP goal
• JNC 7 recommends initial combination therapy in
  patients gt 20/10 mm Hg over goal BP

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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