hypertension 2012: what the latest clinical trials mean to my practice

2nd Annual Primary Care Fall Conference Friday, October 26, 2012

Jan Basile, MDHypertension

Hypertension 2012: What The Latest Clinical Trials Mean to My Practice

Jan Basile, MDSeinsheimer Cardiovascular Health ProgramProfessor of MedicineMedical University of South CarolinaRalph H. Johnson VA Medical CenterCharleston, South Carolina

2nd Annual Primary Care Fall Conference Maui, Hawaii October 25 , 2012

DISCLOSURE OF FINANCIAL RELATIONSHIPS

Jan N. Basile, MDGrant/Research support: NHLBI (SPRINT)

Consultant: Daiichi-Sankyo, Forest, Takeda

Speakers Bureau: Daiichi-Sankyo , Forest, Takeda, Boehringer Ingelheim, Lilly

Major stock shareholder: None

Other: None



Question 1Which of the following statements about hypertension is true?

1) Calcium Channel Blockers are less effective than ACE inhibitors for preventing first stroke.

2) Home BP monitoring is less predictive of CV events than office BP measurement

3) Lifestyle management should only be used in those with pre-hypertension

4) Aliskerin should not be used with an ACEI or ARB in those with AODM-2

5) None of the above are true


1) Atenolol, when used once-a-day, compared to other antihypertensive agents is associated with a reduced risk of stroke.

2) Hydrochlorthiazide, at 12.5-25 mg qd, is associated with improved clinical outcomes.

3) Chlorthalidone is an evidence-based thiazide-like diuretic shown to reduce stroke and CV events.

4) Combination therapy should be reserved for those with white coat hypertension




Your patient has Stage 1 hypertension and no compelling indication. Which of the following antihypertensive drugs has not been shown to improve clinical outcome in evidence-based clinical trials?

1. Lisinopril 40 mg2. Amlodipine 10 mg3. Hydrochlorthiazide 12.5 mg4. Chlorthalidone 25 mg5. They will all improve clinical outcome

Question # 3Choose the Best Answer

Why Are We Still Talking About HTN?

It’s prevalentOver 74 million in U.S. have HTNAbout 70 million in U.S. have prehypertensionIncreasing prevalence with aging of population and epidemic of overweight/obesity

Control of BP leads to a reduction in eventsApproximately 50% reduction in heart failureApproximately 40% reduction in strokeApproximately 20%–25% reduction in MI

Ong KL et al. Hypertension. 2007;49:69.Hebert PR et al. Arch Inten Med. 1993;153:578. Kannel WB. JAMA. 1996;275:1571. Moser M, Hebert P. J Am Coll Cardiol. 1996;27:1214.

HTN, hypertension; BP, blood pressure

j22

j22 NOTE: Our reference format includes only first page number of article (not full page range). Also, no comma before "et al" and refs flush right. Abbreviations and footnotes should not appear in the same text box as refs.jsimmons, 7/31/2010



20-Year Trends in Hypertension in the U.S.: 1988–2008

Hajjar I et al. JAMA. 2003;290:199.Egan BM et al. JAMA. 2010;303:2043.

0

10

20

30

40

50

60

70

80

90

Prevalence Awareness Treatment Control (With RX)

Control (AllHypertension)

%

1988–1991 1991–1994 1999–2000 2007–2008

It's tough to make predictions, especially about the future.

–Y. Berra (1925- )

Trying to Predict JNC 8



Is it the Antihypertensive Class or the BP Achieved That Best Improves

Outcome in Those with Hypertension and No Compelling Indication?

Question 1

0.5 1.0 2.0

BP-Lowering Treatment TrialistsComparisons of different active treatments

Lancet 2003; 360:1903

Relative Risk RR (95% CI)BP Difference

(mm Hg)

FavorsFirst Listed

FavorsSecond Listed

Major CV Events

CV Mortality

Total Mortality

1.02 (0.98, 1.07)2/0ACE vs. D/BB

1.03 (0.95, 1.11)2/0ACE vs. D/BB

1.00 (0.95, 1.05)2/0ACE vs. D/BB

1.04 (0.99, 1.08)1/0CA vs. D/BB

1.05 (0.97, 1.13)1/0CA vs. D/BB

0.99 (0.95, 1.04)1/0CA vs. D/BB

0.97 (0.95, 1.03)1/1ACE vs. CA

1.03 (0.94, 1.13)1/1ACE vs. CA

1.04 (0.98, 1.10)1/1ACE vs. CA



FavorsFirst Listed

FavorsSecond Listed

0.5 1.0 2.0

BP-Lowering Treatment TrialistsComparisons of different active treatments

Lancet 2003; 360:1903

Relative Risk RR (95% CI)BP Difference

(mm Hg)

CA vs. D/BB 1.33 (1.21, 1.47)1/0

0.93 (0.86, 1.01)CA vs. D/BB 1/0

1.01 (0.94, 1.08)CA vs. D/BB 1/0

ACE vs. CA 0.82 (0.73, 0.92)1/1

1.12 (1.01, 1.25)ACE vs. CA 1/1

0.96 (0.88, 1.05)ACE vs. CA 1/1

Stroke

Coronary Heart Disease

Heart Failure

1.09 (1.00, 1.18)ACE vs. D/BB 2/0

0.98 (0.91, 1.05)ACE vs. D/BB 2/0

1.07 (0.96, 1.19)ACE vs. D/BB 2/0

Question 2

What Is The Optimal BP For Outcome Improvement in Special Populations?

DiabeticCKD

Elderly



One Million Adults, 61 Prospective Studies

Ischemic Heart Disease Mortality Stroke Mortality

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

Increasing Systolic Blood Pressure and Age Elevates Risk of Ischemic Heart Disease (IHD) and

Stroke Mortality

Usual Systolic BP (mm Hg)

256

12864

32

16

8

42

1

120 140 160 180

IHD

Mor

talit

y(A

bsol

ute

Ris

k an

d 95

% C

I)

Age at Risk (y)

80-89

70-79

60-69

50-59

40-49

Usual Systolic BP (mm Hg)

256

128

64

32

16

8

4

2

1

120 140 160 180S

troke

Mor

talit

y

(Abs

olut

e R

isk

and

95%

CI)

Age at Risk (y)

80-89

70-79

60-6950-59

Chobanian AV et al. JAMA. 2003;289:2560.Arauz-Pacheco C et al. Diabetes Care. 2003;26:S80.

Flack JM et al. Hypertension 2010;56:780. Bakris GL et al. Am J Kidney Dis. 2000;36:646.

Condition mm HgEssential HTN <140/90

DM <130/80

Chronic renal disease <130/80

JNC7/ADA/NKF/ISHIB Guidelinesfor Hypertension

Guidelines Have Set Clear Treatment Goals

140/90

130/80

ADA, American Diabetes Association; NKF, National Kidney Foundation; ISHIB, International Society on Hypertension in Blacks



Why is it important not to intensify medications to reduce BP below the level

proven in trials?

• It identifies a much larger proportion of the US population as having “hypertension” and presumably need drug therapy [i.e, all diabetics > 130].

• Millions previously classified as having “HTN”require more drugs to achieve lower BP goals.

• Even if neither beneficial nor harmful, resources would be wasted and patient adherence could suffer.

• Treating to lower BP levels may be harmful (J-curve?).


DiabeticCKD

Elderly



SBPUKPDSADV

UK Prospective Diabetes Study, BMJ Volume 321, August 12, 2000.

ACCORD


DiabeticCKD

Elderly



Trial Phase Trial and CohortPhases Cohort Phase

p=0.16

p=0.01

Cum

ulat

ive

Inci

denc

e, %

Standard control-Dotted Intensive control-Solid

>300 mg/day HR 0.73, 95% CI, 0.58–0.93

Effect of Level of BP Control on CumulativeIncidence of the Composite Primary Outcome According to

Baseline Proteinuria Status

300 mg/day HR 1.18, 95% CI, 0.93–1.50

Follow-up Year>300 mg/dayStandard control 176 165 134 113 81 66 45 32 26 22 13Intensive control 181 172 151 128 109 87 67 56 47 40 25

300 mg/day Standard control 376 373 362 353 332 302 267 234 214 196 128Intensive control 357 350 335 321 306 282 254 228 206 189 128

Adapted with permission from Appel LJ et al for the AASK Collaborative Research Group. N Engl J Med. 2010;363:918–929.

Systematic Review: BP Target in CKD Proteinuria as an Effect Modifier

• Evidence does not conclusively show that the currently recommended BP target of < 130/80 mm Hg improves clinical outcomes more than a conventional target of <140 mm Hg.

• A lower target may be beneficial in persons with proteinuria > 300 to 1000 mg/d.

• We suggest that practitioners use discretion in patients with CKD and proteinuria and base the BP target on individualized risk-benefit assessment. Treatment to a lower target may require greater vigilance to monitor for and avoid possible symptoms and adverse events from hypotension.

Upadhyay, A et al. Ann Intern Med 2011;154:541-548.




DiabeticCKD

Elderly

BP Targets and Achieved BP in HTN Intervention Studies in Elderly

1. SHEP Cooperative Research Group. JAMA. 1991;265(24):3255-3264. • 2. Staessen JA, et al. Lancet. 1997;350(9080):757-764. • 3. Beckett NS, et al; for HYVET Study Group. N Engl J Med. 2008;358(18):1887-1898.

SHEP1 Syst-Eur2 HYVET3

Subjects, n 4736 4695 3845

Inclusion BP Criteria, mm Hg 160-219/< 90 160-219/< 95 160-190/< 110

Goal SBP, mm Hg < 160 or 20 mm reduction

< 150 or 20 mm reduction < 150

Mean Achieved BP, mm Hg 143/68 151/79 144/78

Follow-up, y 4.5 (mean) 2.0 (median) 1.8 (mean)



• Systolic BP values <140 mm Hg are appropriate goals for most patients <80 years of age; for 80 years of age, a goal of < 150 mm Hg is acceptable aiming for 140-145 mm Hg, if tolerated.

ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly

Aronow WS et al. ACCF/AHA 2011 Expert Consensus Hypertension in the Elderly. J Am Coll Cardiol. Volume 57, No 20 pg 2037-2114. May 17, 2011

Condition mm Hg

Essential HTN <140/90

DM 130-134/80

Chronic kidney disease

Elderly

< 140/90

< 130/80 with clinical proteinuria

< 140 if age 79 or less; < 150 shooting for 140-144 mm Hg if age > 80

JNC 8 Guidelines?

140/90

130/80



Question 3

What Antihypertensive Medications Should Be Recommended as Initial

Therapy?

Compelling Indications for Individual Drug Classes

Diuretic-

blocker ACEI ARB CCBAldo

Antag. Clinical Trial Basis

HF

ACC/AHA HF guideline; MERIT-HF; COPERNICUS, CIBIS, SOLVD; AIRE, TRACE, Val-HeFT; RALES

Post-MIACC/AHA post-MI guideline; BHAT; SAVE, CAPRICORN, EPHESUS/VALIANT

High CAD Risk

ALLHAT; HOPE, ANBP2; LIFE; CONVINCE, ONTARGET

Diabetes NKF-ADA guideline; UKPDS; ALLHAT

CKD NKF guideline; CAPPP; RENAAL; IDNT, REIN, AASK

Stroke PROGRESS, LIFE

Chobanian AV et al. JAMA. 2003;289:2560-2572.

MI=myocardial infarctionCKD=chronic kidney disease



Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg)

Thiazide-type diuretics for most May consider ACEI, ARB,

-blocker, CCB, or combination

In Patients With Hypertension

INITIAL DRUG CHOICES

LIFESTYLE MODIFICATIONS

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or CKD)

Optimize dosages or add additional drugs until goal blood pressure is achievedConsider consultation with hypertension specialist

Drug(s) for the compelling indications Other antihypertensive drugs

(diuretics, ACEI, ARB, -blocker, CCB)as needed

Not at Goal Blood Pressure

In Patients With Compelling Indications Related to Hypertension

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)

2-drug combination for most(usually thiazide-type diuretic andACEI or ARB or -blocker or CCB)

Management of Blood Pressure

Adapted from Chobanian AV et al. Hypertension. 2003;42:1206–1252.

Years to CHD Event0 1 2 3 4 5 6 7

Cum

ulat

ive

CH

D E

vent

Rat

e

0

0.04

0.08

0.12

0.16

0.20RR (95% CI) p value

A/C 0.98 (0.90–1.07) 0.65

L/C 0.99 (0.91–1.08) 0.81

ChlorthalidoneAmlodipineLisinopril

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Non-fatal MI) by ALLHAT Treatment Group

Adapted with permission from ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2981–2997.



ALLHAT Secondary Endpoints: Heart Failure* Rate Lower in Diuretic vs. ACEI or CCB

*Heart failure is a component of combined cardiovascular disease.Adapted from ALLHAT Collaborative Research Group. JAMA. 2002;288:2981–2997.

1.38 (1.25–1.52)

RR (95% CI)

Favors AmlodipineFavors Lisinopril

Heart failure (fatal, non-fatal, hospitalized or treated)

1.19 (1.07–1.31)AmlodipineLisinopril

Hospitalized/fatal heart failure1.35 (1.21–1.50)1.10 (0.98–1.23)

AmlodipineLisinopril

Favors Chlorthalidone

0.5 2.01

JNC-8: What Might Be Expected?

• Either a thiazide-type diuretic, CCB, ACEI/ARB will be recommended as initial drug therapy for most patients. Direct renininhibitors will be recommended as an additive but not first line agent

• Chlorthalidone or indapamide should be highlighted as the evidence-based thiazide-type diuretic of choice

Moser M, Basile J, Kaplan M, and Victor R. Med Roundtable Cardiovasc Ed. 2010 pg 267-275.



Dose-Response Curve With HCTZ: Have We Gone Too Far With Low-Dose HCTZ?

Compared with HCTZ 25 mg ABP: P = NS vs 12.5 mg (both systolic and diastolic), P=0.0001 vs50 mg systolic, and P = NS vs 50 mg diastolic. N indicates number of patients.

24-H

r BP

Cha

nge

(mm

Hg)

0

-6

-12-14

-4

-8-10

-2

5 Studies(N=123)50 mg

9 Studies(N=503)25 mg

4 Studies(N=129)12.5 mg

-3.3-5.7

Systolic ambulatory BP (ABP)Diastolic ABP

-5.4

-7.6

-5.4

-12

Messerli FH et al. J Am Coll Cardiol. 2011:57:590.

NS, not significant

Evidence for Chlorthalidone

MRFIT C or HCTZ vs usual careTOMHS C vs enalapril, amlodipine (A)

doxazosin (D), acebutolol, and placebo

SHEP C vs placeboALLHAT C vs lisinopril, A, and D

1.MRFIT Grimm RH Jr et al. Arch Intern Med. 1985;145:1191.2.MRFIT Circ ulation1990;82:1616.3.MRFIT Hypertension 2011;57;689.4.TOMHS Neaton JD et al. JAMA. 1993;270:713.5.SHEP Cooperative Res Group. JAMA 1991; 265:3255.6.ALLHAT Collaborative Research Group. JAMA 2002; 288: 2981.



12.411.4

13.5

7.4 8.16.4

-16-14-12-10-8-6-4-20

CLD 25 mg HCTZ 50 mg

Chlorthalidone Has Greater BP-Lowering Efficacy vs HCTZ, Especially at night

CLD=chlorthalidone; HCTZ=hydrochlorothiazide.

Red

uctio

n in

Mea

n SB

PB

asel

ine

to W

eek

8, m

m H

g24-hour Mean SBP Daytime Mean SBP Night-time Mean BP

Daytime was 6:00 AM to 10:00 PM; night-time, 10:00 PM to 6:00 AM.

P=0.009P=0.054 P=0.230

Ernst ME, et al. Hypertension. 2006;47:352-358.

Chlorthalidone Has a Longer Half-life and Duration of Action vs. HCTZ

Half-life, hours Duration of Action, hours

Single dose Long-term dosing Single dose Long-term

dosing

HCTZ 6-9 8-15 12 16-24

CLD 40 45-60 24-48 48-72

Carter BL, et al. Hypertension. 2004;43:4-9



Aliskerin

– FDA Approved at 150 or 300 mg– as initial or additional therapy – ALiskerin Trial In Type 2 Diabetes Using CV

and Renal Disease Endpoints (ALTITUDE)- Aliskerin vs placebo on top of ACEI or ARB in type 2 diabetes with renal impairment

- stopped early when DMSB noted more nonfatal strokes, renal complications, hyperkalemia, and hypotension over 18-24 months follow-up

- still awaiting final publication– No outcomes available as initial antihypertensive

Future Evidence for Aliskerin

ASTRONAUT AliSkerin TRial ON Acute Heart Failure oUTcomes

ATMOSPHERE Aliskerin Trial to Minimize OutcomeS in Patients with HEart failuRE

APOLLO Aliskerin in the Prevention Of Later Life Outcomes

Gheorghiade M, et al. Eur J Heart Fail. 2011; 13: 100-106. Krum H, et al. Eur J Heart Fail. 2011; 13: 107-14.



Lifestyle Modification—Especially Diet and Exercise

Algorithm for BP Control in Non-Compelling Situation(May Start with 2-Drug Combination)

Not at Goal

All Patients

(ACEI or ARB) or ThiazideDiuretic

(Use alternative not used above)

(Mineralocorticoid Receptor Blocker)

(Vasodilatory BB)

Not at Goal

or Amlodipine or Non-AtenololBB

Trials With Initial -BlockersAtenolol• Coope & Warrender• MRC-Elderly• HAPPHY (Atenolol)• Dutch TIA• TEST• UKPDS• LIFE• ELSA• CONVINCE• INVEST• ASCOT

Other -blocker(s)• IPPPSH (oxprenolol)• MRC-I (propranolol)• HAPPHY (metoprolol,

propranolol?)• MAPPHY (metoprolol)• STOP-1 (mixed)• Yurenev (propranolol)• CAPPP (mixed)• STOP-2 (mixed)• NORDIL (mixed)• AASK (metoprolol)



Primary Prevention – MRC Older AdultsCoronary Events

Cumulative % of events

Follow-up (y)

Atenolol

Placebo

Hctz + Amiloride

MRC Working Party, Br Med J. 1992;304:405-12.

P=0.0009

10

8

6

4

2

0

0 1 2 3 4 5 6 7

ASCOT-BPLAELSAINVESTLIFEMRC OldUKPDSTotal events

0.5 0.7 1 1.5 2

Atenolol Other drug RR RR(n/N) (n/N) (95% Cl) (95% Cl)

422/961814/1157

201/11309309/4588

56/110217/358

1019/28132

327/96399/1177

176/11267232/460545/108121/400

810/28169

1.29 (1.12–1.49)1.58 (0.69–3.64)1.14 (0.93–1.39)1.34 (1.13–1.58)1.22 (0.83–1.79)0.90 (0.48–1.69)1.26 (1.15–1.38)

Favorsatenolol

Favorsother drug

-Blocker Meta-analysisStroke: Atenolol vs Other Antihypertensive Agents

ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm; CI, confidence interval; ELSA, European Lacidipine Study on Atherosclerosis; INVEST, International Verapamil-Trandolapril Study; LIFE, Losartan Intervention For Endpoint reduction; MRC, Medical Research Council; RR, relative risk; UKPDS, United Kingdom Prospective Diabetes Study.

Lindholm LH et al. Lancet. 2005;366(9496):1545-1553.



Beta-Blockers and Reduced Protection Against Stroke

• Adverse metabolic effects: – Increased insulin resistance and weight gain– Increased triglyceride levels– Reduced HDL cholesterol

• Less effective reduction in central aortic pressure than other treatments

• Enhanced blood pressure variability relative to other treatments

Isn’t this just a problem with atenolol?What about other beta-blockers?

• No data in RCTs with regard to the effectiveness of other beta-blockers in preventing major cardiovascular outcomes and mortality in hypertensive patients

• The absence of data does not mean absence of effectiveness, but without evidence there can be no recommendation when we have such effective alternatives

• Pathophysiologically, the less-effective stroke prevention, less-effective reduction in central pressure, and increase in BP variability are likely to be a function of heart rate lowering and an increase in pulse pressure in the context of a stiff aorta in older people (ie, applicable to all drugs with this mechanism of action)



NICE Treatment of Hypertension Update 2011

New Cost-Effectiveness Reviewof Drug Therapy for Hypertension

NICE. Clinical guidelines (CG127). August 2011. Available at: http://www.nice.org.uk/nicemedia/live/13561/56007/56007.pdf. Accessed May 8, 2012.

Cost Effectiveness of Antihypertensive Treatment 2011

No intervention Thiazide-type diuretics Calcium-channel blockersBeta-blockers ACE inhibitors/angiotenson-II receptor antagonists

4,800

4,600

4,400

4,200

4,000

3,8009.40 9.60 9.80 10.00 10.20 10.40

Mean Effect (QALYs Per Person, Discounted)

Mea

n C

ost (

2009

UK

Per P

erso

n, D

isco

unte

d)

1,960

5,400

5,200

4,800

4,600

4,400

4,2009.80 10.00 10.20 10.40 10.60 10.80

Mean Effect (QALYs Per Person, Discounted)

1,520

5,000

Men Women

“Treating high blood pressure is cheaper than doing nothing”

“Beta-blockers are the least cost-effective treatment….apart from no treatment at all” Bryan Williams 2011

Base case results (65-year-old, 2% cardiovascular risk, 1.1% diabetes risk, 1% HF risk)

NICE. Clinical guidelines (CG127). August 2011. Available at: http://www.nice.org.uk/nicemedia/live/13561/56007/56007.pdf. Accessed May 8, 2012.



Antihypertensive Drug Treatment AlgorithmNICE 2011

Age <55 yrs Age 55 yrs or black*

Step 1 A C†

A + C†Step 2

A + C + D Step 3

A + C + D + further diuretic‡

Consider specialist advice

Step 4Resistant Hypertension

NICE. Clinical guidelines (CG127). August 2011. www.nice.org.uk/CG127. Accessed May 8, 2012.

*Of African or Caribbean family origin

†CCB preferred but D is an alternative in people intolerant of C or at high risk of heart failure

‡Consider low-dose spironolactone or higher-dose thiazide

A = angiotensin-converting-enzyme inhibitor or angiotensin receptor blockerC = calcium channel blockerD = thiazide-like diuretic

National Institute for Health and Clinical Excellence (NICE) Places -Blockers as Fifth-Line Treatment for

Uncomplicated Hypertension

NICE Clinical Guideline 127, August 2011.

• Beta-blockers are not a preferred initial therapy for uncomplicated hypertension.

• If treatment with three drugs is required, the combination of ACEinhibitor or ARB, calcium-channel blocker and thiazide-like diuretic should be used.

• Beta-blockers may be considered in younger people, particularly:-those with an intolerance or contraindication to ACE inhibitors and ARB’s -women of child-bearing potential-people with evidence of increased sympathetic drive.

• If therapy is initiated with a beta-blocker and a second drug isrequired, add a calcium-channel blocker rather than a thiazide-likediuretic to reduce the person’s risk of developing diabetes.



Conclusions• The NICE decision to relegate beta-blockers

from initial therapy to special indications was fully justified due to:

– Less effective stroke prevention than alternative treatments

– No more effective prevention of other major cardiovascular events

– Less desirable metabolic profile than other treatments

– Beta-blockers are the least cost-effective option for hypertension treatment on formal analysis

Question 4When should 2 or more antihypertensive agents be recommended as initial therapy, either as a fixed-dose combination (FDC) or as 2 individual agents?

Which 2 drug combinations have the greatest BP-lowering effect?



0.19

Incr

emen

tal

SB

P re

duct

ion

ratio

of

obs

erve

d to

exp

ecte

d ad

ditiv

e ef

fect

s

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

Combining Drugs from Different Classes is Approximately 5 Times More Effective in Lowering

BP than Doubling the Dose of 1 Drug

1.00

0.60

0.40

0.20

0

1.40

0.80

1.20

Guideline Recommendations Regarding Initial Use of Combination Therapy

JNC 7 >20/10 mm Hg

ISHIB >15/10 mm Hg

ESH >20/10 mm Hg OR high cardiovascular risk

AHA SBP 160 mm Hg or DBP 100 mm Hg irrespective of the BP goals

NKF K/DOQI SBP >20 mm Hg above goal according to the stage of CKD and CVD risk

JNC 7, Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.ISHIB, International Society on Hypertension in Blacks.ESH, European Society of Hypertension.AHA, American Heart Association.NKF K/DOQI, National Kidney Foundation Kidney Disease Outcomes Quality Initiative.1. Chobanian AV, et al. Hypertension. 2003;42:1206-1252. 2. Douglas JG, et al. Arch Intern Med. 2003;163: 525-541. 3. K/DOQI. Am J Kidney Dis. 2004;43 (suppl 1):S65-S230. 4. Mancia G, et al. J Hypertens. 2007;25:1105-1187. 5. Rosendorff C, et al. Circulation. 2007;115;2761-2788.



• 45 practices (2048 patients) in southern Ontario randomized to:

Guideline-based “stepped” care

– Based on Canadian Health System Guidelines(similar to JNC 6)

STITCH care algorithm

– Start ½ tab single-pill fixed-dose combination of ACEI-diuretic or ARB-diuretic

– Increase dose of combination tablet

– Add calcium channel blocker

– Add a peripheral alpha blocker, beta blocker or spironolactone

• Primary Outcome = Proportion at BP target at 6 months

The Simplified Therapeutic Intervention To Control Hypertension (STITCH) Trial—Methods

Feldman RD, et al. Hypertension. 2009;53(4):646-653.

STITCH STUDY: Main Results (Summary)

Variable Usual Care STITCH P-Value# of patients 1246 802Baseline

SBP, mmHg 153.4 155.1 NSDBP, mmHg 87.7 88.1 NSDiabetic, % 15.9 15.1 NSFDC, % 9.3 11.2 NSBP control, % 0 0 NS

Final visitSBP, mmHg -17.5 -22.6 <0.005DBP, mmHg -8.2 -10.4 <0.05

FDC, % 15 85 <0.001Med titration, % 69.6 82.6 <0.01BP control, % 52.7 64.7 <0.05

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



The Simplified Therapeutic Intervention To Control Hypertension (STITCH) Trial—Results

95% CI: 1.5% to 22.4%P=0.026

Feldman RD, et al. Hypertension. 2009;53(4):646-653.

52.764.7

0

10

20

30

40

50

60

70

Guideline-Based Care STITCH-Based Care

Control Rates (%)6-Month Follow-up

Gradman AH, Basile JN, Carter BL, Bakris GL; American Society of Hypertension Writing Group. J Am Soc Hypertens. 2010;4:42.

Drug Combinations in HTN: Recommendations

Preferred• ACE inhibitor/diuretic*• ARB/diuretic*• ACE inhibitor/CCB*• ARB/CCB*

Acceptable

• BB/diuretic*• CCB (dihydropyridine)/BB• CCB/diuretic• Renin inhibitor/diuretic*• Renin inhibitor/ARB*

• Thiazide diuretics/K+ sparing diuretics*

Less effective

• ACE inhibitor/ARB• ACE inhibitor/BB• ARB/BB• CCB (nondihydropyridine)/BB• Centrally acting agent/BB

*Single-pill combinations available in the United States.



Hermida et al. Hypertension. 2009.

Bedtime Dosing of One BP Medicationin Resistant Hypertension

3 drugs on awakeningOne of the drugs at bedtime

Cha

nge

in S

BP (

mm

Hg)

-12-15-8-6-4-202

Diurnal mean Nocturnal mean 24-hr mean

P<0.001 P<0.001 P<0.001

Cha

nge

in D

BP (m

m H

g)

-12-15-8-6-4-202

P<0.001 P<0.001 P<0.001

Clinical Points• It makes less difference which antihypertensive

agent is used, unless the patient has a compelling indication for a specific antihypertensive class, and matters more that BP is appropriately reduced to the chosen BP goal.

• The current recommended BP goals in those with Diabetes and CKD from the ADA, NKF, and JNC 7 is <130/80 mm Hg. Evidence may change the JNC 8 recommendations.

• The initial drug chosen will be broadened to include Thiazide-diuretic, ACEI/ARB, or CCB.



Clinical Points• Most patients will require 2 or more

antihypertensive agents to get BP effectively controlled which may be best approached with initial combination therapy, either as a fixed-dose combination (FDC) or as 2 individual initial agents

















2) Hydrochlorthiazide, at 12-25 mg qd, is associated with improved clinical outcomes.




hypertension 2012: what the latest clinical trials mean to my practice

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