Initial Combination Treatment in Hypertension: Who Are the CandidatesGeorge Bakris, MD, F.A.S.H., F.A.S.N.Professor of MedicineDirector, Hypertensive Disease UnitUniversity of Chicago, Pritzker School of MedicineChicago, IL

Monotherapy for Hypertension Is Inadequate in ~40% to 50% of Patients

*Response = DBP <90 mm Hg at the end of titration period and having maintained a DBP of <95 mm Hg for 1 year without drug tolerance.Mean baseline BP = 152/99 mm Hg.Adapted from Materson BJ et al. Am J Hypertens. 1995;6:189-192.

72

62 6055 54 50

31

0

20

40

60

80

100

50% response

Patie

nts

With

Res

pons

e* (%

)

CCB(dilitiazem)

α2 Agonist (clonidine)

β-blocker(atenolol)

Diuretic(HCTZ)

α1 Antagonist(prazosin)

ACEI(captopril)

Placebo

Rationale for Fixed-Dose Combination Therapy: Background• Traditional antihypertensive therapy yields goal BP in

<60% of treated hypertensive patients1-3

• Switching from one monotherapy to another is effective in only about 50% of patients1

• Most patients will require at least two drugs to attain goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic renal disease)4-6

BP = blood pressure1. Materson BJ et al. J Hum Hypertens. 1995;9(10):791-796.2. Messerli FH. J Hum Hypertens. 1992;6 Suppl. 2:S19-S21.3. Ram CV. J Clin Hypertens (Greenwich). 2004;6(10):569-577.4. Chobanian AV, et al. JAMA. 2003;289(19):2560-2572.5. Guidelines Committee. J Hypertens. 2003;21:1011-1053.6. American Diabetes Association. Diabetes Care. 2002;25(Suppl.1):S71-S73.

Monotherapy

Fixed-Dose Combination

89.3%

10.7%

88.6%

11.4%

88.0%

12.0%

87.6%

12.4%

Growth of Fixed-Dose Combinations

IMS National Prescription Audit (NPA)

0.19

Incr

emen

tal S

BP

redu

ctio

n ra

tio

of o

bser

ved

to e

xpec

ted

addi

tive

effe

cts

Thiazide

Wald DS et al. Am J Med. 2009;122:290-300.

Beta blocker

Calcium channel blocker

Adding a drug from another class (on average standard doses)Doubling dose of same drug (from standard dose to twice standard)

1.041.00

1.16

0.89

1.01

0.20.23

0.37

ACE inhibitor

All classes

0.22

Ratio of Observed to Expected Incremental BP-Lowering Effects of Adding a Drug or

Doubling the Dose According to Drug Class

1.00

0.60

0.40

0.20

0

1.40

0.80

1.20

SBP=systolic blood pressure. *Target blood pressure control groups in ACCORD defined as <120 mm Hg (intensive) and <140 mm Hg (standard).Updated from Bakris G et.al Am J Kidney Dis 2000.The ACCORD Study Group. N Engl J Med. 2010 Mar 14. [Epub ahead of print]

ACCOMPLISH 131ALLHAT 138HOT 138

ACCORD (intensive)* 119ACCORD (standard)* 133INVEST 133IDNT 138RENAAL 141ABCD 132UKPDS 144

MDRD 132AASK 128

Multiple Medications Are Required to Achieve BP Control in Clinical Trials

Hyper-tension

Diabetes

Kidneydisease

No. of BP medications1 2 3 4

SBP achieved (mm Hg)Trial

Adherence and Pill Burden

Odds of Being Adherent to Both Lipid- and BP-Lowering Rx

0.72 0.680.55

0

0.2

0.4

0.6

0.8

1

1.21.0

0–1 2–3 8+4–7

Odd

s R

atio

Chapman RH et al. Circulation. 2003;108(17 suppl IV):IV-756-757.

Number of Medications in Addition to Lipid- and BP-Lowering Rx

Improved Adherence With Fixed-Dose Combination Therapy Compared With

Free-Combination Therapy

*P<.0001.MPR = number of days of therapy for medication dispensed 365 days of study follow-up.Gerbino PP, Shoheiber O. Am J Health-Syst Pharm. 2007;64:1279-1283.

•Because this was a retrospective analysis of administrative claims data, patients were not randomly assigned and could not be matched by any empirical methods. Although we know the prescriptions were filled based on these claims data, it is unknown if patients specifically took the medication as prescribed.•Levels of disease severity as defined by clinical measurements were not available within the design of the study.•Analyses of concomitant drug classes were used to estimate disease severity, as polypharmacy may affect adherence. Other factors may exist that might have influenced selection or use of antihypertensive agents, which could not be captured or assessed in the study.

Fixed-Dose Combination (ACEI/CCB)

Free Combination (ACEI+CCB)

(n=2839)

(n=3367)

*

Medication Possession Ratio (MPR)

88

69

0 20 40 60 80 100

Compliance Gap Between Fixed-dose Combination and Dual Agent Regardless of Concomitant Medications

90.2%89.6%87.7%88.8%

86.5%87.3%85.9%

67.2% 65.6%

72.1%69.7%70.1%

73.6%73.7%

50%

60%

70%

80%

90%

100%

1 2 3 4 5 6 >6

Fixed-doseDual agent

Med

icat

ion-

poss

essi

on ra

tio (M

PR)

Number of concomitant drugs

* ***

*

*p=<0.0001

**

US pharmacy claims data (n=6,206)

Wanovich. Am J Hypertens 2004;17:223A

Adherence With Fixed-Dose Combinations Compared With Free-Drug Combinations

Bangalore S et al. Am J Med. 2007;120:713-719.Risk Ratio

0.1 1 10

Risk Ratio (95% CI) % Weight

0.89 (0.51,1.57) 0.6 0.88 (0.55,1.42) 1.1 0.78 (0.55,1.11) 1.5 0.74 (0.67,0.81) 25.3 0.74 (0.65,0.84) 12.9 0.81 (0.77,0.86) 43.2 0.71 (0.62,0.80) 11.7 0.50 (0.35,0.71) 3.1 0.47 (0.22,1.01) 0.6

0.76 (0.73,0.79)

Study Su WJ et al Geiter LJ et al Eron JJ et al Taylor AA et al Dezii CM et al NDC Dataset Dezii CM et al Melikian C et al Melikian C et al

Overall (95% CI)

Adapted from Mancia et al. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension. J Hypertension 2007; 25(9): 1751-62

Diuretics

ACE inhibitors

Calciumantagonists

AT1-receptorblockers-blockers

-blockers

Preferred Combinations

Concomitant Use of Antihypertensive Drugs

Controversial Combinations

*Beta- or alpha- blockers, clonidine, loop diuretics

14 Days Day 1 Month 1 Month 2 Year 5

ScreeningAmlodipine 5 mg +benazepril 20 mg

Ran

dom

izat

ion

Benazepril 40 mg + HCTZ 12.5 mg

Benazepril 40 mg + HCTZ 25 mg

Free add-on antihypertensive agents*

Month 3

Free add-on antihypertensive agents*

Amlodipine 5 mg +benazepril 40 mg

Amlodipine 10 mg +benazepril 40 mg

Benazepril 20 mg + HCTZ 12.5 mg

Titrated to achieve BP <140/90 mmHg or <130/80 mmHg with diabetes/renal insufficiency

ACCOMPLISH: DesignN = 11,462 with systolic hypertensionand CV or renal disease or targetorgan damage

Jamerson KA et al. Am J Hypertens. 2004;17:793-801; Presented at: ACC 2008 Chicago; ClinicalTrialResults.org.

mm

Hg

Month

5757 5408 5222 5033 4825 4299 2529 10425740 5404 5178 5010 4866 4298 2804 1074

Patients

ACEI / HCTZN=5733

CCB / ACEIN=5713

131.6 mmHg

132.5 mmHg

Difference of 0.9 mmHg p<0.001

DBP: 73.3 DBP: 74.4

ACCOMPLISH – Blood Pressure Results

Jamerson et al. NEJM. 2008; 359(23); 2417-2428.

Cum

ulat

ive

even

t rat

e

HR (95% CI): 0.80 (0.72, 0.90)

20% Risk Reduction

Time to 1st CV morbidity/mortality (days)

p = 0

ACEI / HCTZ

CCB / ACEI679

552

.0 01

ACCOMPLISH – Primary Endpoint

Jamerson et al. NEJM. 2008; 359(23); 2417-2428.

STITCH: Objective and Study Design

2104 patients from 45 Primary Care Practices in Southern Ontario

Primary endpoint: Proportion of patients reaching BP target(practice-level) at 6 months

STITCH-Care Algorithm(18 Practices)

Guideline-Care Algorithm(27 Practices)

Objective: To assess if the use of a fixed-dose combination (FDC) as initial treatment of hypertension will improve the proportion of patients reaching goal BP as compared to the use of the Canadian Hypertension Education Program (CHEP) algorithm

Design:

Feldman RD et al. Hypertension. 2009;53:646-653.

STITCH: Study Design (cont’d)CHEP Guidelines:

Treatment of hypertension withoutother compelling indications

Target: SBP <140 DBP <90 mm Hg

STITCH –Care Algorithm

BP controlled?NoYes

Initial therapy with a low dose ACE-diuretic or ARB/diuretic

combination

Continue with current therapy

Up-titrate combination therapy successively to

the highest dose

Add calcium channel blocker and up-titrate

Continue with current therapy

Continue with current therapy

Add alpha blocker, beta-blocker or spironolactone

Yes

Yes

No

No

Feldman RD et al. Hypertension. 2009;53:646-653.

Lifestyle Modification

Therapy

Thiazide Diuretic

ACE-I ARB Long-acting CCB

Beta-blocker

Dual Combination

Triple or Quadruple Therapy

Variable Usual Care STITCH P valueN 1246 802

Baseline SBP (mm Hg) DBP (mm Hg) Diabetic (%) FDC (%) BP control (%)

153.487.715.99.30

155.188.115.111.2

0

NSNSNSNSNS

Final visit D SBP (mm Hg) D DBP (mm Hg) FDC (%) Med titration (%) BP control (%)

-17.5-8.215

69.652.7

-22.6-10.4

8582.664.7

<0.005<0.05<0.001<0.01<0.05

STITCH: Main Results

Feldman RD et al. Hypertension. 2009;53:646-653.

STITCH: Predictors of AchievingBP Target

*The analysis was conducted using a modified Poisson regression model that evaluated patient-level data.†P values were derived by adjustment for clustering in the model.Feldman RD et al. Hypertension. 2009;53:646-653.

Univariate Analyses Multivariate Model

DeterminantRisk Ratio 95% CI P*†

Risk Ratio 95% CI P*†

STITCH-care 1.2 1.02 to 1.40 0.03 1.2 1.0 to 1.4 0.03

Age (per 10 yr increase) 1.0 0.97 to 1.06 0.48

Female 1.0 0.86 to 1.03 0.22

Not diabetic 2.5 2.02 to 3.05 <0.001 2.5 2.0 to 3.1 <0.001

Physician before 1984 1.1 0.88 to 1.26 0.63

Conclusions• Monotherapy is the standard initial

treatment for reducing BP, with stepwise increases in dose if the desired decrease in BP is not achieved

• Combining drugs from different classes is approximately 5 times more effective in lowering BP than increasing the dose of 1 drug

• Combination therapy is the preferred initial strategy in the treatment of high BP

Gradman AH et al. J Am Soc Hypertens 4:42-50, 2010.

DRUG COMBINATIONS IN HYPERTENSION: RECOMMENDATIONSPreferred

ACE inhibitor/diuretic* ARB/diuretic* ACE inhibitor/CCB* ARB/CCB*

Acceptable Beta blocker/diuretic* CCB (dihydropyridine)/β-blocker CCB/diuretic Renin inhibitor/diuretic* Renin inhibitor/ARB* Thiazide diuretics/K+ sparing diuretics*

Unacceptable ACE inhibitor/ARB ACE inhibitor/β-blocker ARB/β-blocker CCB (nondihydropyridine)/β-blocker Centrally acting agent/β-blocker

*SPC available in the US