# Presentation: 819690

## 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 Hypertension and the Benefits of Treatment

**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.

**Hypertension Increases****Morbidity and Mortality**

**Treatment Decreases****Morbidity and Mortality**

## 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 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 Not New

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

## Current Antihypertensive Therapy Reduces CV Events

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

**Average Reduction in Events, %**

**Major CV **
**Events**

**20%****–****30%**

**Stroke**

**30%****–****40%**

**CV Death**

**30%****–****40%**

**–****60**

**–****40**

**–****20**

**0**

**–****100**

**–****80**

## CV Mortality Risk Doubles WithEach 20/10 mm Hg BP Increment*

- 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 WithEach 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 With Up to a 40% Effect on 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 BP (Data from Multiple Clinical Trials Measuring the Impact of Hypertensive Therapy on Cardiovascular Mortality)

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

**MRC2**

**MIDAS/NICS/VHAS**

**UKPDS C vs A**

**NORDIL**

**INSIGHT**

**HOT L vs H**

**HOT M vs H**

**MRC1**

**HEP**

**EWPHE**

**STOP1**

**ATMH**

**PART2/SCAT**

**CAPPP**

**Syst-China**

**0.25**

**0.50**

**0.75**

**1.00**

**1.25**

**1.50**

**Syst-Eur**

**STONE**

**UKPDS L vs H**

**RCT70-80**

**Odds Ratio (experimental/reference)**

***P=*****0.002**

**Cardiovascular Mortality**

**–****5**

**0**

**5**

**10**

**15**

**20**

**25**

**Difference (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**

## Multiple Antihypertensive Agents Are Needed to Achieve Target BP

- Number of antihypertensive agents

- 1

- Trial

- 2

- 3

- 4

- Multiple Antihypertensive Agents Are 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 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

*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 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 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)

- 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)

- 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