Hypertension trials

HypertensionHypertension

Clinical Trial Summary SlidesClinical Trial Summary Slides

www.cardiosource.com

77

84

0

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80

100

ACCEPT

Stabilized BP

%

Trial Design: Prospective, surveillance study to determine the efficacy and safety of quinapril asmonotherapy or in combination with other antihypertensive medications at lowering blood pressureover 6-month follow-up among Canadian patients with essential hypertension.

Clinical Therapeutics 1994; 5:838-53

Results• Stabilized BP attained in 77% of patients at 3 months and 84% of patients at 6 months• At least one adverse event reported in 26.2% of patients• Adverse events ↑ in patients given a more detailed side effect form (30% vs 24%, p=0.004)

Conclusions• In actual clinical practice among community-dwelling Canadian patients with essential hypertension, quinapril seemed safe and effective at decreasing blood pressure either alone or in combination with other antihypertensive medicationsn= n=

N=2979 N=2517

3 months 6 months


Results• Antihypertensive agent used in 78% of patients• At end of treatment, BP ↓ in active acupuncture group vs sham acupuncture group (Figure; between group difference in SBP/DBP 6.4 / 3.7 mm Hg, p < 0.001)• No difference in blood pressure between groups at 3 and 6 month follow-up, with blood pressures returning to pretreatment levels in active treatment groupConclusions• Among patients with mild or moderate arterial hypertension, active acupuncture therapy was associated reduction in blood pressure at treatment end compared with sham acupuncture therapy• Effect of intervention did not last beyond active treatment timeframe• Despite use of traditional Chinese medicine techniques to lower blood pressure, limited data available from randomized trials to show such an effect• Additional studies warranted to validate findings, which may provide alternative treatment method for patients with mild arterial hypertension

8078

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30

60

90

125130

0

30

60

90

120

150

Acupuncture for Lowering Blood Pressure

DBP Post-Treatmentp < 0.001

mm

Hg

Trial Design: The study was a randomized trial of active acupuncture (n = 72) or sham acupuncture (n = 68) for6 weeks, conducted in 22 sessions lasting 30 minutes in patients with mild or moderate arterial hypertension.Primary endpoint was average systolic and diastolic blood pressure on 24-hour ambulatory blood pressuremonitoring after the treatment course and at 3 and 6 months.

Circulation. 2007;115:epub before print

Active acupuncture Sham acupuncture

SBP Post-Treatmentp < 0.001


6.3

8.9 9.3

11.8 11.5

0

5

10

15

Placebo

Results• Reduction in SBP and DBP ↑ for all treatment groups vs placebo (Figure)• Reduction in BP in aliskiren 300 mg and 600 mg group ↑ vs irbesartan 150 mg group (p<0.05)• Controlled BP met in more patients in irbesartan 150 mg group (33.8%) and aliskiren 150 mg (37.8%), 300 mg (50.0%) and 600 mg (45.7%) than placebo group (20.8%; p<0.05 for each comparison)• Adverse event rates similar between treatment groupsConclusions• Among patients with mild-to-moderate hypertension,once-daily treatment with novel oral renin inhibitoraliskiren was associated with greater reduction in SBPand DBP compared with placebo• Additionally, aliskiren 300 mg and 600 mg associatedwith greater reductions in BP compared with irbesartan• Safety profile similar between treatment groups

Aliskiren in Hypertensive Patients

Change from baseline in trough mean sitting DBP

p<0.05 for each vs placebo

mm

Hg

Trial Design: Patients with mild-to-moderate hypertension were randomized in a double-blind manner to once-daily oral aliskiren 150 mg (n=127), aliskiren 300 mg (n=130), aliskiren 600 mg (n=130), irbesartan 150 mg(n=134), or placebo (n=131). Primary endpoint was change from baseline in trough mean sitting DBP.

Circulation. 2005;111:1012-1018

Irbesartan 150 mg

Aliskiren

300 mg

600 mg


Results• Mean baseline blood pressure 154/100 mm Hg• At follow-up, blood pressure (SBP/DBP) ↓ by 4.6/4.1 mm Hg in placebo group, 13.0/9.0 mm Hg in aliskiren group, 12.8/9.7 mm Hg in valsartan group, and 17.2/12.2 mm Hg in combination group (p < 0.001 for combination vs. placebo and for combination vs. each individually)• Blood pressure control highest in combination group (Figure)• Adverse event rate similar between groupsConclusions• Among patients with mild to moderate hypertension, aliskiren, valsartan, and the combination were associated with greater reductions in blood pressure compared with placebo at 8 weeks, with largest reductions seen in combination group• Both aliskiren and valsartan inhibit renin-angiotensin-aldosterone system, but act at different points in system, with aliskiren acting at point of activation• Both agents were effective in ↓ blood pressure, but combination of two agents appeared to be additive

16.5

37.433.8

49.3

0

20

40

60

Aliskiren and Valsartan for Antihypertensive Therapy%

Trial Design: The study was a randomized, double-blind trial of aliskiren (150 mg; n = 437), valsartan (160 mg;n = 455), the combination of the two (n = 446), or placebo (n = 459) in patients with mild to moderatehypertension. Primary endpoint was reduction in mean sitting DBP at 8 weeks.

Presented at ACC/i2 Summit 2007

Placebo Aliskiren

Blood Pressure Controlp < 0.05 for combination vs. placebo and

for combination vs. each individually

Aliskiren+Valsartan

Valsartan


17.3 16.8 17.2

0

5

10

15

20

n=9048

11.5 11.3 11.4

0

5

10

15

20

n=15255

7.7

10.2

8.7

0

5

10

15

20

ALLHAT

Fatal heart disease or MIRR A vs C = 0.98, p=0.65RR L vs C = 0.99, p=0.81

%

Trial Design: ALLHAT was a NHLBI sponsored, 623 site, blinded randomized trial of the diureticchlorthalidone vs the calcium channel blocker amlodipine and the ACE inhibitor lisinopril in patientswith hypertension. Patients were followed for a mean of 4.9 yrs. Primary endpoint (EP) was fatal heartdisease or nonfatal MI.

All Cause MortalityRR A vs C = 0.96, p=0.20RR L vs C = 1.00, p=0.90

JAMA 2002;288:2981-2997

Results• No difference in prespecified 1° endpoint• Lower heart failure rate (2° EP) with chlorthalidone vs amlodipine or lisinopril• Lower stroke rate (2° EP) with chlorthalidone vs lisinopril(RR 1.15 p=0.02)• Higher glucose levels with chlorthalidone vs amlodipine or lisinopril• All 3 drugs reduced blood pressure from baseline, but SBP reduction greater with chlorthalidone Conclusions• No difference in fatal heart disease or MI• Benefit for chlorthalidone in heart failureEPLimitations

• Important side effect in the chlorthalidone arm was higher fasting glucose levels• Impact of chlorthalidone on diabetes and CV disease may not be fully manifested in the relatively short follow-up of 4 years • ACE-I arm may be disadvantaged since the 1st add-on therapy specified was beta-blocker rather than diuretic or Ca blocker• Relatively large crossover rate

Chlorthalidone (C) Amlodipine (A) Lisinopril (L)

% %

Heart FailureRR A vs C = 1.38, p<0.001RR L vs C = 1.19, p<0.001

n=9054


14.9 15.3

9.310.4

5.3 5.8

0

5

10

15

20

ALLHAT-LLT

All-cause mortalityRR = 0.99, p=0.88

%

Trial Design: ALLHAT Lipid Lowering Trial was a non-blinded randomized substudy of the NHLBIsponsored ALLHAT antihypertensive trial. Moderately hypercholesterolemic, hypertensive patients wererandomized to pravastatin or usual care and followed for a mean of 4.8 yrs. The primary endpoint wasall-cause mortality.

Fatal Heart Diseaseor Nonfatal MIRR = 0.91, p=0.16

JAMA 2002;288:2998-3007

Results• No difference in prespecified 1° endpoint or 2°endpoints (fatal heart disease or nonfatal MI, stroke, heart failure, cancer)• Greater benefit in blacks than in nonblacks with pravastatin for fatal heart disease or nonfatal MI endpoint (RR 0.73 vs 1.02, p=0.03)• Crossover from usual care to statin treatment increased from 8% at year 2 to 17% at year 4• Total cholesterol by 17.2% in pravastatin arm and by 7.6% in usual care arm by year 4Conclusions• Despite moderate reduction in cholesterol with pravastatin, there was no difference in mortality, CHD or stroke compared with usual care for moderate hypercholesterolemia• Lack of clinical benefit with statin therapy contrasts with other large statin trials (4S, CARE, LIPID, and PROSPER)• Meta-analysis of 9 large statin trials including ALLHAT-LLT shows CHD events 27% and mortality 14% with statin therapyLimitations

• High rate of statin use in usual care arm• Non-blinded trial

Pravastatin Usual Care

StrokeRR = 0.91, p=0.31

n=5170 n=5185


56.159.8

41.945.7

15.7 17.1

0

20

40

60

ANBP2

All cardiovascularEvents or Mortality

RR = 0.89, p=0.05

Rat

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r 1,

000

patie

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ear

Trial Design: The ANBP2 Trial was a non-blinded randomized trial of ACE inhibitors vs diuretic therapyin elderly hypertensive patients. Patients were followed for a median of 4.1 yrs. The primary endpointwas all cardiovascular events or all-cause mortality.

First cardiovascularEvents or Mortality

RR = 0.89, p=0.06

N Engl J Med 2003;348:583-592

Results• Primary endpoint with ACE inhibitor vs diuretic• Benefit with ACE inhibitor in primary endpointobserved in men (RR 0.83, p=0.02) but notwomen (RR 1.00, p=0.98)• Similar benefit with ACE therapy observed for 2endpoint of first cardiovascular events (HR 0.88,p=0.07) and first MI (HR 0.68, p=0.04)• Mortality did not differ between the arms (HR0.90, p=0.27)Conclusions• Among older patients with hypertension,treatment with ACE inhibitors was associated withbenefit in composite of all-cause death orcardiovascular events at 4 year follow-up• Results of ANBP2 trial differ from recentlypublished ALLHAT trial, which reported nodifference in 1 endpoint between diuretic armand ACE inhibitor arm (using lisinopril)• Meta-analysis of new hypertensive trials pendingLimitations• Non-blinded trial• Gender-stratified results was a post-hoc analysisand should be interpreted as such

ACE Inhibitor Diuretic

All causeMortality

RR = 0.90, p=0.27

n=3044 n=3039

www.cardiosource.comAtenolol/

bendroflumethiazide

Results• SBP at study end slightly ↓ in amlodipine/perindopril group (Figure)• Randomized medication: 73% atenolol, 67% bendroflumethiazide, 78% amlodipine and 63% perindopril• Trial stopped early due to efficacy in amlodipine/perindopril group • Primary endpoint trended ↓ in amlodipine/perindopril group (HR 0.90, p=0.12)• Several prespecified 2° endpoints ↓ in amlodipine/ perindopril group, including all-cause mortality (HR 0.86, p=0.005), all coronary events (HR 0.86, p=0.0048), all cardiovascular events and procedures (HR 0.84, p<0.0001), stroke (HR 0.77, p=0.0007), and CV mortality (HR 0.76, p=0.0017)Conclusions• Among patients with hypertension, a strategy of treatment withamlodipine and perindopril if needed was associated with reductionsin many secondary endpoints, including mortality, compared withtreatment with the beta-blocker atenolol and the diureticbendroflumethiazide, prompting the trial to be discontinued early inorder to substitute appropriate alternative antihypertensive therapy inthe beta-blocker group

135.5 136.3

0

50

100

150

ASCOT – Blood Pressure Arm

SBP at study end

mm

Hg

Trial Design: ASCOT was a multicenter, randomized trial of treatment with a calcium channel blocker(amlodipine 5 mg; n=9639) with or without an ACE-I (perindopril 4 mg) compared with a beta-blocker (atenolol50 mg; n=9618) with or without a diuretic (bendroflumethiazide 1.25 mg) in hypertensive patients. Primaryendpoint was nonfatal MI and fatal coronary heart disease at follow-up of 5.4 years.

Presented at ACC 2005

Amlodipine/perindopril


Endpoint HR p-valueCV Death/MI 0.64 0.0005

Stroke 0.73 0.0236

CV events 0.79 0.0005/procedures

All-cause 0.87 0.1649mortality

ASCOT Lipid Arm

Lancet 2003;361:1149-58

Results• Lipid-lowering limb of trial discontinued early due significant reduction in primary endpoint of non-fatal MI and fatal coronary disease • Both total cholesterol and LDL-CH at 3 year follow-up were 1.0 mmol/L lower in the atorvastatin arm vs placebo• All pre-specified subgroups favored atorvastatin arm with no heterogeneity in any subgroupConclusions• Among patients with hypertension and relatively low cholesterol, treatment with atorvastatin was associated with non-fatal MI and fatal coronary disease at 3 year follow-up• ASCOT results in line with other large statin trials such as 4S, CARE, LIPID, and PROSPER, all of which demonstrated a benefit in morbidity and/or mortality with statin therapy

Trial Design: ASCOT was a randomized, double blind factorial trial of treatment with atorvastatin(10 mg) (n=5168) or placebo (n=5137) in hypertensive patients with a total cholesterol <6.5 mmol/lwho were also enrolled in the open-label anti-hypertensive arm of the ASCOT trial. The primaryendpoint was non-fatal MI and fatal coronary disease by a median follow-up of 3.3 years.

1.00.5 1.5


Results• Persistent microalbuminuria development ↓ in trandolapril plus verapamil group and trandolapril alone group vs placebo but did not differ for verapamil group vs placebo group (Figure)• Average SBP and DBP, respectively was 139 and 80 mm Hg in combination group, 139 and 81 mm Hg in trandolapril group, 141 and 82 mm Hg in verapamil group, and 142 and 83 in placebo group (p<0.002 for combination group vs placebo and trandolapril vs placebo; p=NS for verapamil vs placebo)• Nonfatal SAEs similar by treatment groupsConclusions• Among patients with hypertension, type 2 diabetes, and normal urinary albumin excretion, treatment with trandolapril plus verapamil and trandolapril alone were associated with a reduction in development of microalbuminuria compared to placebo, while treatment with verapamil alone was not associated with a reduction in development of microalbuminuria compared with placebo

5.7 6.0

11.9

10.0

0

5

10

15

BENEDICTTrial Design: BENEDICT was a randomized, double-blind trial of the ACE-inhibitor trandolapril (2 mg/day) plusthe calcium channel blocker verapamil (180 mg/day) (n=300), trandolapril alone (2 mg/day) (n=301), verapamilalone (240 mg/day) (n=303), or placebo (n=300) among patients with hypertension, type 2 diabetes, and normalurinary albumin excretion. Primary endpoint was development of persistent microalbuminuria.

N Engl J Med 2004;351:2302-9

Trandolapril + verapamil Trandolapril

Development of persistent microalbuminuriap = 0.01 for trandolapril + verapamil vs placebo

p = 0.01 for trandolapril vs placebo p = 0.54 for verapamil vs placebo

%

Placebo

Verapamil


Atenolol/bendroflumethiazide

Results• No difference in brachial SBP by treatment group (133.2 mmHg for amlodipine vs 133.9 mmHg for atenolol group, p=NS), but DBP slightly ↓ in amlodipine group (76.9 vs 78.6 mmHg, p<0.001)• Area under curve for central SBP ↓ in amlodipine group (121.2 vs 125.5 mmHg, p<0.001) • Central pulse pressure ↓ with amlodipine (Figure), while brachial pulse pressure did not differ (55.3 vs 56.2 mmHg, p=0.06)Conclusions• Among hypertensive patients, treatment with regimen of calciumchannel blocker with or without ACE inhibitors was associated withreductions in central systolic blood pressure and pulse pressurecompared with regimen of beta-blocker with or without diuretic,despite no difference in brachial blood pressure• Small reductions in brachial SBP in overall trial withamlodipine/perindopril strategy not large enough to account forentire clinical benefit• Present substudy suggests that reductions in blood pressuremay have been greater than originally estimated when assessedusing brachial artery evaluation

43.446.4

0

10

20

30

40

50

CAFE

Central Pulse Pressurep<0.001

mm

Hg

Trial Design: CAFE was a substudy (n=2073) of the ASCOT trial, a randomized trial of treatment with a calciumchannel blocker (amlodipine 5 mg) with or without an ACE-I (perindopril 4 mg) compared with a beta-blocker(atenolol 50 mg) with or without a diuretic (bendroflumethiazide 1.25 mg) in hypertensive patients. In CAFE,central aortic blood pressure was assessed.

Presented at AHA 2005

Amlodipine/perindopril


10.4 10.7

16.3

0

10

20

30

CALM %

redu

ctio

n in

dia

stol

ic B

P

Trial Design: The CALM trial was a prospective, randomized, parallel-group, double-blind trialdesigned to assess the effects of candesartan, lisinopril or both on blood pressure and urinaryalbumin excretion in patients with type 2 diabetes, hypertension and microalbuminuria.

BMJ 2000;321:1440-1444

Results• At 24 weeks, mean reduction in diastolic blood pressure with combination treatment was significantly greater than that with candesartan or lisinopril (Figure)• Reduction in urinary albumin:creatinine ratio with combination treatment greater than that with candesartan and lisinopril (Figure)• Treatment was well tolerated in all groupsConclusions• Among patients with microalbuminuria, hypertension, and type 2 diabetes, treatment with combination therapy with candesartan and lisinopril was associated with a reduction in blood pressure as well as having a beneficial effect on albuminuria and was associated with an good safety profile.Candesartan

groupLisinopril

group

6466

Mean reduction in diastolic blood pressure

24

39

50

0

10

20

30

40

50

60

Mean reduction in Urinary albumin:creatinine

ratio

Combination group

67 %re

duct

ion

in u

rinar

y al

bum

in:c

reat

inin

e

66 64 67


-8.0

-9.5

-13

-11

-9

-7

-5

-3

-1

CANDLEC

hang

e in

sitt

ing

DB

P, m

mH

g

Trial Design: CANDLE was a multicenter, double-blind, randomized trial that comparedantihypertensive effects of two angiotensin receptor blockers (ARB), candesartan cilexetil(n=160) and losartan (n=169), among patients with systemic hypertension. Primaryendpoint: change in week 8 of trough sitting DBP.

Week 4 Week 8p = 0.019

Heart Dis 1999;1:52-7

Results• Decrease in DBP at 8 weeks ↑ in

candesartan group (Figure)• DBP controlled in slightly more patients in

candesartan group at 4 weeks• Similar rate of adverse effects in two

groupsConclusion• In a diverse hypertensive population,

therapy with candesartan 16 to 32 mg/day was associated with significantly greater DBP reduction, compared to losartan 50 to 100 mg/day

Limitations• Medications were not force-titrated to

maximum dose, so full effect of the two medications could not be directly compared Losartan

n=169Candesartan cilexetil

n=160

-8.9

-11.0-13

-11

-9

-7

-5

-3

-1


0.30 0.29

0.0

0.1

0.2

0.3

0.4

CAPARES

Loss in lumendiameter

%

Trial Design: CAPARES was a multicenter randomized, double-blinded, placebo-controlledclinical trial (n=635) designed to investigate the effect of amlodipine (10 mg/day) on restenosisand clinical outcomes in patients undergoing Percutaneous Transluminal CoronaryAngioplasty (PTCA). Primary endpoint: loss in minimum lumen diameter (MLD) at 4-monthangiographic follow-up.

JACC 2000; 35(3): 592-9

Results• PTCA performed in 92.1% of patients, with stents implanted in 15.6% of patients.• Both groups achieved similar acute gains in MLD.• No differences in loss of MLD (0.30 mm with amlodipine vs. 0.29 mm with placebo, p=NS) or in restenosis (28.1% vs. 28.4%, p=NS).• Rates of repeat PTCA and composite of death, MI, CABG, and repeat PTCA among patients treated with amlodipine (3.1% vs. 7.3% for repeat PTCA, p=0.02; 9.4% vs. 14.5% for composite endpoint, p=0.049).Conclusions• Treatment with amlodipine was not associated with a reduction in angiographic restenosis, but was associated with reduced repeat PTCA procedures.• These results are attributable to the anti-ischemic effects of amlodipine, and do not support the routine use of this medication in the prevention of restenosis after PTCA.

Amlodipine Placebo

3.1

7.3

0

2

4

6

8

10

RepeatPTCA

215236 318 317

P=NS P=0.02%


4.5 4.4

0

1

2

3

4

5

1.5

1.2

0.0

0.5

1.0

1.5

2.0

CONVINCE

Stroke, MI, or CV deathHR 1.02

(95% CI 0.88-1.18)p=0.77

%

Trial Design: CONVINCE was a randomized trial of controlled onset-extended release (COER)-verapamil (180mg/day; n=8241) or standard of care (n=8361), defined as either hydrochlorothiazide (HCTZ, 12.5 mg) oratenolol (50 mg) in hypertensive patients with at least 1 risk factor. Patients were followed for a mean of 3years. The primary endpoint was stroke, MI, or CV death at follow-up, and the trial was designed to assessequivalence.

Heart FailureHR 1.30

(95% CI 1.00-1.69)p=0.05

JAMA 2003;289(16):2073-2082

Results• Trial stopped early by sponsor due to commercial considerations before unblinding results• 40% of patients discontinued blinded study medication in each arm at close of trial•Upper bound of 95% CI for the primary endpoint (HR 1.18) exceeded prespecified boundary (HR 1.16) for equivalence• No significant differences in the individual components of the composite: MI HR=0.82, p=0.09; stroke HR 1.15, p=0.26; CV death HR=1.09, p=0.47• Heart failure hospitalizations in verapamil arm (HR 1.30, p=0.05)Conclusions• Among hypertensive patients with at least 1 risk factor, CONVINCE trial did not demonstrate equivalence in 1endpoint of long acting verapamil-based therapy vs a regimen of the diuretic HCTZ or beta-blocker atenolol• Given early trial discontinuation by sponsor, limited conclusions can be drawn from the study• Results similar to those observed in ALLHAT, which showed calcium channel blocker amlodipine was not superior to diuretic chlorthalidone in reducing coronary heart disease or stroke and was associated with inheart failure

COER-verapamil Hydrochlorothiazideor atenolol

%


15.1

8.9

14.0

6.5

0

5

10

15

20

EUTOPIA

Reduction in Inflammatory Markersfrom Baseline to 6 weeks

in Olmesartan Patients

% re

duct

ion

Trial Design: The EUTOPIA trial was a randomized, double-blind trial of 12 weeks of therapy with theARB-II receptor antagonist olmesartan (20 mg; n=100) or placebo (n=99) among patients with essentialhypertension. All patients received pravastatin (20 mg/d) after 6 weeks. The primary endpoint wasinflammatory markers at 6 and 12 weeks.

Results• Baseline inflammatory markers high in both olmesartan andplacebo groups• At 6 week follow-up (prior to the addition of pravastatin to thetreatment regimen), inflammatory markers were significantly lowerin the olmesartan arm compared to baseline, including hsCRP(p<0.05), hsTNF-alpha (p<0.02), IL-6 (p<0.05), and MCP-1(p<0.01; Figure)• No change from baseline in inflammation markers in placeboarm• No difference from baseline in inflammation markers inpravastatin alone group (ie, cotherapy with placebo) at 12 wks• Need for HCTZ to control blood pressure in olmesartan groupvs placebo (21.0% vs 42.4%)Conclusions• Among patients with essential hypertension, treatment withangiotensin II receptor antagonist olmesartan was associated withreduction in inflammatory markers compared with placebo• However, addition of pravastatin after 6 weeks of placebotherapy was not associated with reduction in inflammatorymarkers but was associated with reduction in LDLhsCRP hsTNF-alpha

Circulation. 2004;110:1103-1107

IL-6

MCP-1


-9.1

-2.0

-10

-5

0

Results• Mean change in HbA1c from baseline ↑ in metoprolol group vs carvedilol (Figure)• Study drug discontinuation due to worsening glycemic control ↑ in metoprolol group (2.2% vs 0.6%, p=0.04)• Reduction in HOMA-IR from baseline greater in carvedilol group (Figure) • Triglyceride ↑ greater in metoprolol group (13.2% vs 2.2%, p<0.001)Conclusions• Among patients with hypertension and type 2 diabetes taking a renin-angiotensin system blocker, treatment with carvedilol was associated with more stabilized glycemic control and improved insulin resistance compared with metoprolol when used to acheive target blood pressure goals• Larger trial would be needed to determine if improvements in glycemic control and insulin resistance with carvedilol would translate into differences in clinical outcomes

0.02

0.15

0.0

0.1

0.2

GEMINI

Change in HOMA-IRfrom Baseline

p = 0.004

Trial Design: GEMINI was a randomized, double-blind study of the effect of beta-blocker administration withcarvedilol (6.25 to 25 mg dose, twice daily) (n=498) or metoprolol tartrate (50 to 200 mg dose, twice daily)(n=737) on glycemic control among patients with hypertension and type 2 diabetes. Primary endpoint waschange from baseline HgA1C following 5 months of maintenance therapy.

Presented at AHA Scientific Sessions 2004

Carvedilol Metoprolol

Change in HbA1cfrom Baseline

p < 0.001

%


4843

35 33

0

10

20

30

40

50

6064

5045 45

0

10

20

30

40

50

60

70

HANE

n=215

n=220

% a

chie

ving

goa

l DB

P

HANE was a multi-center, randomized, double-blind trial of atenolol, enalapril,hydrochlorothiazide, and nitrendipine in patients with hypertension. 868 patients werefollowed for an eight-week titration period where dosage was increased as needed.Patients that achieved DBP<90mmHg at 8 weeks were followed for an additional fortyweeks. The primary outcome measure was ability to reduce DBP<90 mmHg.

BMJ 1997;315:154-159

Results• Achievement of BP goal ↑ in atenolol group at 8 weeks (Figure)• At 48 weeks, achievement of BP goal in atenolol group ↑ than HCTZ and nitrendipine groups but not significantly different from enalapril group (Figure)• Dropout due to adverse events significantly ↑ in nitrendipine arm (n=28) vs atenolol (n=11), enalapril (n=12), and hydrochlorothiazide (n=9)Conclusions• Among hypertensive patients, treatment with atenolol was associated with improved DBP control at 8 weeks compared to hydrochlorothiazide, enalapril, and nitrendipine

n=215

n=218

8 weeks 48 weeks

Atenolol Enalapril HCTZ Nitrendipine


Results• In sibutramine vs placebo group, reduction ↑ for body weight (Figure), BMI (Figure) and waist circumference (5.0 vs. 0.8 cm; p < 0.0001)• Findings consistent in antihypertensive therapy cohorts but were not as great in metoprolol/HCT group• Reductions in office SBP / DBP not different between sibutramine and placebo groups (-5.9 / -0.7 mm Hg vs. -4.8 / -2.3 mm Hg, p = NS)• Heart rate ↑ in sibutramine group vs placebo (+4.5 bpm -1.4 bpm, p < 0.0001), a finding consistent in all 3 antihypertensive therapy cohortsConclusions• Among obese hypertensive patients, sibutramine therapy was associated with greater weight loss at 16 weeks compared with placebo, with attenuation of weight loss in metoprolol/hydrochlorothiazide cohort• Sibutramine, previously shown to be effective for weight loss in obese patients, is a monoamine reuptake inhibitor, which may cause ↑ in blood pressure and thus offset any decrease in blood pressure associated with weight loss

0.5

2.0

0

1

2

3

5.7

1.5

0

2

4

6

8

HOS

Reduction in BMIp < 0.001

kg

Trial Design: HOS was a randomized trial of sibutramine (15 mg; n = 87) or placebo (n = 84) in obesehypertensive patients receiving 1 of the 3 antihypertensive combination therapies (felodipine 5 mg/ramipril 5mg, n =57; verapamil 180 mg/trandolapril 2 mg, n = 55; or metoprolol succinate 95 mg/hydrochlorothiazide 12.5mg, n = 59). Primary endpoint was weight loss at 16 weeks.

Circulation. 2007;115:1991-1998

Sibutramine Placebo

Reduction in Body Weightp < 0.001

kg/m

2


9.9 10.2

7.8 7.9

1.2 1.3

0

2

4

6

8

10

12

INVEST

Death/MI/StrokeRR 0.98p=0.57

%

Trial Design: INVEST was a randomized, open label trial of treatment with the calcium antagonistverapamil SR (n=11,267) or the non-calcium antagonist atenolol (n=11,309) in patients with hypertensionand coronary artery disease. Patients were followed for a mean of 2.7 years. The primary endpoint wasnon-inferiority for the composite of all-cause mortality, non-fatal MI or non-fatal stroke.

Deathp=0.72

Results• Trial met pre-specified hypothesis of non-inferioritywith verapamil for death, MI or stroke (Figure0• No difference in any component of composite• New onset diabetes in verapamil arm (7.03% vs8.23%, p<0.05)• Primary endpoint+new onset diabetes inverapamil arm (14.63% vs 16.25%, p<0.05)• More than half of patients using >3 drugs at follow-up (51% and 52%, respectively)Conclusions• Among hypertensive CAD patients, treatmentstrategy with calcium antagonist verapamil was non-inferior for all-cause mortality, MI and strokecompared with treatment with a non-calciumantagonist strategy with atenolol• Majority of patients in each arm treated with >3drugs at follow-up, indicating complexity of therapyrequired in patients with both hypertension and CAD• New onset diabetes reduction noteworthy;however, it was not a pre-specified endpoint andshould be considered hypothesis generating, not aconclusive treatment effect

Strokep=0.33

Verapamil Atenolol n=11,267 n=11,309

JAMA 2003;290 2805-2816


84.1 82.776.4

0

20

40

60

80

100

Low Blood Pressure and Cardiovascular Morbidity in Treated Hypertensive Patients: INVEST Substudy

Death/MI/Stroke

mm

Hg

Trial Design: INVEST was a randomized, open label trial of treatment with the calcium antagonistverapamil SR (n=11,267) or the non-calcium antagonist atenolol (n=11,309) in patients with hypertensionand coronary artery disease. Primary endpoint was non-inferiority for composite of all-cause mortality,non-fatal MI or non-fatal stroke at mean of 2.7 yrs follow-up.

MI

Results• Target blood pressure goal met by 72% of verapamilgroup and 71% of atenolol group• Curve for relation of SBP and CV events slightly Jshaped although minimally• Curve for relation of DBP and CV events moresharply J shaped• For DBP, nadir for primary endpoint was 84.1 mmHg, for MI was 82.7 mm Hg and for stroke was 76.4mm Hg, suggesting DBP below these thresholds wasassociated with adverse events• Ratio of MI to stroke gradually as DBP below 70mm HgConclusions• Among high-risk patients with hypertension andCAD, DBP was related to adverse clinical events inform of a J shaped curve, with excessively low DBPconferring increased risk as well excessively highDBP• Such a relation was weakly observed with SBP, withmuch flatter curve than with DBP

Stroke

Presented at ACC Scientific Sessions 2004

DBP Nadir by Events


5.2

9.7

14.9

0

5

10

15

20

IRMA 2%

Trial Design: IRMA 2 was a prospective, randomized, placebo-controlled multi-center studydesigned to evaluate the renoprotective effect of the angiotensin-II-receptor antagonistirbesartan in hypertensive patients with type 2 diabetes and microalbuminuria. The patientswere randomly assigned to receive Irbesartan (150 mg/day or 300 mg/day) or placebo. Medianfollow up was 2 years.

N Engl J Med 2001;345:870-8

Results• Baseline characteristics in three groups were similar• Nephropathy (defined by persistent proteinuria in overnight specimens, with a urinary albumin excretion rate greater than 200 μg/min, and at least 30% higher than baseline level) developed in 30 patients in placebo group vs 19 patients in 150-mg group (p=0.08) and 10 patients in 300-mg group (p<0.001) (Figure)• After adjustment for baseline microalbuminuria and blood pressure achieved during the study, the hazard ratio for nephropathy was 0.56 in the 150-mg group (95% CI, 0.31 to 0.99, p=0.05) and 0.32 in the 300-mg group (95% CI, 0.15 to 0.65, p<0.001)Conclusions• Among hypertensive patients with type 2 diabetes and persistent microalbuminuria, treatment with irbesartan was associated with a significant reduction in the rate of progression to overt diabetic nephropathy Irbesartan 300 mg group Irbesartan 150 mg group

21

34

24

0

10

20

30

40

Restoration ofNormoalbuminuria

p=0.006for the 300 mg group

195194

%

Placebo group

201

Overt Nephropathyp=0.08 for the 150 mg group,

p<0.001 for the 300 mg group

201195194


LIFE

Lancet 2002; 359: 995-1003.

%

Results• BP by 30.2/16.2 in losartan arm and 29.1/16.8 in atenolol arm (p=0.017 for SBP; p=0.37 for DBP)• Primary composite endpoint in losartan arm (Figure), as was stroke and new onset diabetes but no difference in CV mortality (Figure)Conclusions• Unlike CAPPP, NORDIL and STOP-HTN2 trials which compared ACE inhibitors or calcium channel blockers with beta blockers and diuretics for treatment of hypertension, LIFE showed a significant treatment effect with use of the angiotensin II type 1-receptor antagonist losartanLimitations• High risk HTN patients selected for study; generalizability to lower risk patients cannot be made• No comparison of losartan to diuretic

Trial Design: LIFE was a multi-center randomized trial of losartan (an ARB) compared with atenololalone in prevention of coronary events in patients with hypertension (HTN) and LVH. Mean follow-upwas 4.8 yrs. Primary endpoint was a composite of death, MI and stroke.

11

13

45 5

76

8

0

5

10

15

20

Losartan Atenolol

PrimaryComposite

HR 0.87p=0.021

CVMortalityHR 0.89p=0.206

Stroke

HR 0.75p=0.001

New onsetDM

HR 0.75p=0.001


159

138152

135

0

30

60

90

120

150

180

MATH

Baseline Therapy

Diabeticsp <0.0001

n=154

Sitti

ng S

BP,

mm

Hg

MATH was a multi-center, observational trial of nifedipine gastrointestinal theraputicsystem (GITS) in patients with mild to moderate hypertension. Patients were followed for12 weeks of therapy. Primary endpoint was reduction in systolic blood pressure.

n=735

Non Diabeticsp < 0.0001

Am J Hypertens 1990;3:333S-341S

Results• Study enrolled broad range of patients, including diabetics (157) and obese (458)• Blood pressure ↓ in all subgroups including those with diabetes and obesity (Figure)• No significant ∆ in serum lipids• No significant ∆ in serum glucose among obese or diabetic patients• No adverse effects on renal or electrolyte parameters• Most common adverse event edema (8.6%)Conclusions• Nifedipine GITS associated with significant BP ↓ among broad cohort of patientsLimitations• Observational only; no control arm

Baseline Therapy


8.6

10.3

0

5

10

15

NICS-EH

Nicardipine Trichlormethazide

p = 0.923

Hypertension. 1999;34(5):1129-33

n=204 n=210

%

Results• Similar rate of cardiovascularcomplications in both groups (Figure)• Low occurrence of major side effectsConclusions• Among elderly patients with mild tomoderate hypertension, treatment with adihydropyridine-class calcium channelantagonist was associated with similarrate of cardiovascular complicationscompared with a thiazide-type diureticLimitations• Small sample size did not allow foranalysis of individual cardiovascularendpoints

Trial Design: NICS-EH was a randomized trial evaluating the efficacy of the calcium antagonistnicardipine 20 mg twice daily compared with the diuretic trichlormethazide 2 mg daily in elderlypatients with mild-moderate hypertension. Patients were followed for up to 5 years. Primaryendpoint was cardiovascular complications.

Cardiovascular complications


Results• As intended, weight did not change with different diets (86 kg)• SBP ↓ with all 3 diets, but reduction greater in protein diet and unsaturated fat diet vs carbohydrate diet (Figure)• Likewise, reductions in LDL greater with protein diet (-14.2 mg/dL; p=0.01) and non-significantly with unsaturated fat diet (-13.1 mg/dL, p=0.20) vs carbohydrate diet (-11.6 mg/dL)• Estimated 10 year CHD risk based on the Framingham risk score lowered by 21% for protein diet, 20% for unsaturated fat diet, and 16% for carbohydrate dietConclusions• Among individuals with hypertension or prehypertension, use of modified reduced carbohydrate DASH diet was associated with greater reductions in blood pressure and lipid parameters compared with use of standard DASH diet• DASH diet previously shown to be effective for reducing blood pressure and lipid parameters but substantial portion of DASH diet is made up of carbohydrates (58%)• Present study confirms BP and lipid reductions found in earlier trials with standard DASH diet, but also showed additional reductions possible by substituting more protein or unsaturated fats for some carbohydrates

8.2

9.5 9.3

0

4

8

12

OmniHeart Feeding Study

SBP reductionsp=0.002 for protein vs carb

p=0.005 for unsaturated fat vs carb

mm

Hg

Trial Design: The trial was a randomized, crossover study (n=164) of the DASH diet with the standardcarbohydrates, the protein modified diet, or the unsaturated fat modified diet in patients with hypertension orprehypertension. Patients were on each diet for 6 weeks at which time they ate pre-prepared meals. Primaryendpoints were systolic blood pressure and LDL cholesterol at the end of each diet period

JAMA. 2005;294:2455-2464

Carbohydrate Protein Unsaturated Fat


6.2

28.6

34.4

0

10

20

30

40

6.6

10.511.1

0

5

10

1526

17

12

0

10

20

30

PREMIER

SBP Reductionp<0.001 for established vs advice

p<0.001 for established+DASHvs advice

mm

Hg

Trial Design: PREMIER was a randomized trial of “established” behavioral intervention therapy (n=268),"established plus DASH diet" (n=269), and "advice only" group (n=273) in patients with above-optimal bloodpressure. The primary endpoint was mean reduction in SBP from baseline to 6 month follow-up.

JAMA. 2003;289:2083-2093

Results• Primary endpoint of change in SBP from baseline to 6 months with established intervention and established + DASH diet vs advice only (Figure)• Similar results seen in pre-specified subgroup of patients with and without hypertension at baseline• Compared with advice only, both established and established plus DASH arms reduced weight >15 lbs (Figure), decreased fat consumption (1.7% advice vs 21.6% established vs 45.7% established + DASH, p<0.001 for both vs advice), and lowered sodium intake to <100 mmol/d (7.9% advice vs 19.8% established vs 12.8% established + DASH, p<0.05 for both vs advice)Conclusions• Among patients with above-optimal blood pressure, use of "established" behavioral intervention therapy and established therapy plus DASH diet was associated with reductions in SBP at 6 month vs advice only• Benefits were observed in both non-hypertensive and hypertensive patients, although disease severity was not so severe as to require medical therapy

Advice only EstablishedTherapy

Established+ DASH diet

% %

Weight loss >15 lbs p<0.001 for established vs advice

p<0.001 for established+DASHvs advice

Hypertensionp=0.01 for established vs advicep<0.001 for established+DASH

vs advice


51.0

39.0

32.8

15.2

20.0

2.0

0

20

40

60

RIS

Cholesterol< 6.0 mmol/L

p = 0.01

% p

atie

nts

Trial Design: RIS was a randomized, open-label, parallel study, designed to compare an aggressivemultiple risk factor intervention strategy (Int, n=235) with usual care (UC, n=227) in male patients withhypertension. Endpoints were smoking cessation, serum cholesterol and diabetes control. Patientswere followed for a mean of 3.3 years.

Stopped smokingp = 0.038

Hemoglobin A1c < 6.0%p = 0.06

J Intern Med. 1994;236:651-9

Results• Good compliance with intervention program (87% at 3.3 years)• Intervention program associated with ↓ in serum cholesterol and smoking, as well as trend towards better glucose control (Figure)• Diastolic blood pressure unchanged• Unexpected reduction in risk of stroke (2.0% vs. 6.7% in usual care group)

Conclusions• Among a cohort of middle-aged hypertensive men, a comprehensive risk factor reduction program was associated with improvements in serum lipid profiles and smoking cessation

Intervention Usual Care


9.59.8

0

2

4

6

8

10

12

7.2

3.7

8.5

6.3

8.4

5.0

0

2

4

6

8

10

SLIP

Reduction in Lipid ValuesAfter 6 monthsp <0.01 vs baseline

n=

%

Trial Design: SLIP is a multi-center, prospective trial of the effect of Verapamil sustained release 240mg daily and Enalapril 20 mg daily on plasma lipid levels among patients with mild or moderatehypertension followed for 6 months.

Drugs 1993; 46:16-23

Results• Systolic BP ↓ 1 month post treatment vs baseline with both verapamil and enalapril (Figure)• Total cholesterol, triglycerides and LDL ↓ at 6 months vs baseline with both verapamil and enalapril (Figure) • HDL levels ↑ vs baseline with verapamil (p<0.01) but not significantly ↑ in enalapril group (+9.5% vs +2.5%, respectively; p<0.01 for comparison of verapamil vs enalapril)

Conclusions• Among patients age <70 years with mild or moderate hypertension without additional cardiac risk factors, treatment with verapamil SR 240 mg and Enalapril 20 mg were both associated with significantly lower blood pressure, triglycerides, total and LDL cholesterol post treatment• Verapamil was further associated with greater increases in HDL compared with enalapril

Total Chol Tryglycerides LDL

Reduction in BPAfter 1 monthp <0.01 vs baseline

n=

%

Verapamil (N = 437)

Enalapril (N = 427)


18.4

11.1

0

10

20

30

SWISH

BB CCB

Dro

p in

sys

tolic

BP,

mm

Hg

SWISH was a multi-center placebo controlled randomized trial of isradipine (n=165)compared atenolol (n=191) in patients with essential hypertension. Patients were followedfor 18 weeks. Primary endpoints were change in blood pressure, side effects, and qualityof life scores.

15.3

10.6

0

10

20

30

Dro

p in

dia

stol

ic B

P, m

mH

g

J Cardiovasc Pharm 1991;18(Supp3): S7-S8

Results• Mean doses: atenolol 64.4 mg/day, isradipine 3.6 mg/day• Blood pressure ↓ with both groups, but atenolol had ↑ effect on BP than isradipine (Figures) • No difference in quality of life scores• Similar total number of side effects• Cold extremities, fatigue and vertigo ↑ for atenolol and swollen legs or feet ↑ for isradipineConclusions• Among patients with essential hypertension, treatment with atenolol monotherapy was associated with greater decrease in blood pressure vs isradipine

BB CCB


TAIM

Hypertension. 1991 Feb;17(2):210-7.

n=

Results• Largest DBP ↓ in weight loss/diuretic and weight loss/bb arms (Table)• Similar DBP ↓ in placbo arm regardless of dietConclusions• Weight loss diet associated with additional DBP reduction among patients on diuretics or beta-blocker• ↓Na/↑K diet associated with little additional DBP reduction over drug treatment alone

TAIM was a multi-center randomized trial of nine different combinations of drug or diettherapy for management of mild diastolic hypertension. Atenolol (50 mgqd),chlorthalidone (25 mgqd), weight loss diet (goal ↓10% baseline weight), or ↓Na/↑K dietwere the interventions. Patients were followed for 6 months. Primary endpoint waschange in diastolic blood pressure.

Usual Diet

Weight Loss

↓Na/↑K Diet

Placbo -8.0 -8. 8 -7.9

Diuretic -10.8 -15.1 -12.2

Atenolol -12.4 -14.8 -12.7

Change in DBP at 6 months(mmHg)


39

26

0

10

20

30

40

50

TONETrial Design: TONE was a multicenter randomized trial designed to evaluate weight loss, reducedsodium intake, combined intervention or usual care among older patients for the treatment ofhypertension. Primary endpoint: Occurrence of high BP at one or more TONE study visits. Medianfollow-up:29 months

JAMA 1998; 279(11):839-846

Results• Antihypertensive therapy stopped in 86.8% of usual care group, 92.6% of sodium reduction, 93.2% of weight loss group and 93.2% of combined intervention group • Freedom of trial endpoints 30 months after attempted withdrawal of antihypertensive therapy ↓ with interventions (Figure)•Among the 328 patients who were off antihypertensive medications at the final visit, percentages for BP control were 71% in sodium reduction group, 63% in weight loss group, 73% in combined group and 65% in usual care group Conclusions• The TONE study showed the safety and efficacy of dietary lifestyle interventions as a means to control BP and decrease the need for antihypertensive medication in older patients with hypertension

Weight loss Usual care

37.8

24.4

0

10

20

30

40

50

291294 487 488

P=0.001 P<0.001

Sodium reduction

%

No Sodium reduction

Freedom from CV events and high BP


2.8

5.6

0

5

10

TOPH IIR

educ

tion

in D

BP

at 6

m, m

mH

gTrial Design: TOPH II was a multicenter, randomized trial designed to test the efficacy ofinterventions promoting weight loss, sodium reduction or both in decreasing BP and theincidence of hypertension in moderately overweight patients with a high-normal level ofdiastolic BP. Primary end-point: Net decrease in diastolic BP. Follow-up: 36-48 months.

Arch Int Med 1997;157(6):657-667

Results• 2382 patients randomized to combined weight loss and sodium reduction (Combined group, n=597), weight loss (WL group, n=595), sodium reduction (SR group, n=594) and usual care (UC, n=596)• All intervention groups showed significant changes in DBP measurements at 6 mo vs UC group (-2.7 0.4 for WL group, -1.6 0.4 for the SR group and -2.8 0.4 for combined group, p<0.001 for all groups)• Only WL group exhibited significant difference in DBP reduction at termination visits compared with UC group (-1 0.4, p=0.02)• At 6 months, incidence of hypertension was 7.3% in UC group, 4.2% in WL, 4.5% in SR group and 2.7% in combined group (2.7%) (p<0.001)• By 48 mo, incidence of hypertension similar in 3 intervention groups (38%) and in each case lower than UC group (p=0.02-0.06)Conclusions• Among overweight adults with high-normal BP, sodium reduction and weight loss were effective in lowering BP and decreasing incidence of hypertension

Usual careCombined Weight

loss andSodium reduction

7.3

2.7

0

5

10p<0.001 p<0.001

Inci

denc

e of

hyp

erte

nsio

n at

6 m

, %


2.0

9.3

0

5

10

15

53

28

0

10

20

30

40

50

60

TRENDTrial Design: TREND was a double-blind, randomized trial evaluating treatment with the ACEinhibitor quinapril (40 mg/d; n=64) compared with placebo (n=65) could ameliorate endothelialdysfunction in normotensive patients with coronary artery disease who were free of leftventircular dysfunction and severe dyslipidemia. Primary endpoint: Change in acetylcholine(Ach)-provoked constriction of target segments from baseline to 6 month angiogram.

Circulation 1996; 94:258-265

Results• No change in acetylcholine constriction response at 6 months in placebo group but quinapril group had less constrictor response (1.6% and 2.3% in each Ach dose) compared to prerandomization response (6.1% and 14.3% in each Ach dose)• Extreme response (abrupt and total occlusion) trended ↓ in quinapril group (Figure)• Frequency of ≥5% improvement in response ↑ in quinapril group in target segments (Figure) Conclusions• Among normotensive patients with coronary artery disease, treatment with quinapril was associated with an attenuatation of impaired endothelial function at 6 months compared with placebo

Quinapril Placebo

p=0.008 p=0.131Extreme response

%

Improvement in Ach of ≥5% at 6 months

%


44

54

0

20

40

60

TRIC

rTPA Placebo

Primary endpointp = 0.19

Am Heart J 1992;124:1419-26

%

Results• No significant between group differences for primary endpoint (Figure) or individual components• During ETT, high risk exercise response (ST↓ and low Wmax) ↓ in rTPA group than placebo at discharge (68% vs. 51%, p=0.03) and 1 month (62% vs. 48%, p=0.09)• No between group differences in number or severity of coronary lesions at 1 month angio• No ↑ in major bleeding in rTPA groupConclusions• Among men with unstable angina or NQWMI, rTPA was associated with ↓ occurrence high risk ETT results but no difference in primary composite clinical endpoint compared to placeboLimitations• Underpowered to detect differences in individual components of primary endpoint

TRIC was a randomized, placebo-controlled, double-blind trial of rTPA vs. placebo inpatients with UA or NQWMI. 205 patients were followed for 1 year. Primary endpoint was acombination of death, MI, urgent revascularization, or indication for revascularizationbased on angiogram done at 30-45 days.


3.1

1.9

0

1

2

3

4

209

157

0

50

100

150

200

250

VERBS

QRS Durationp < 0.05

(ms)

Trial Design: VERBS was a randomized crossover trial of RV apical pacing comparedwith multisite RV apical and high RV septal (VERBS) pacing in 39 patients with dilatedcardiomyopathy and AV-block. Pts. were followed for 30 days in each pacing mode.Primary endpoints were echo parameters and clinical status at 30 days.

PACE 2001;24:1369-76.

Results• QRS, EF, MR with VERBS (Figures)• QOL and NYHA Class with VERBSConclusions• Bifocal RV stimulation was associated with improved ventricular function and clinical statusLimitations• Small study, 14/39 patients with Chagas’ disease

RV apex VERBS

32.9

36.9

0

25

50 Ejection fractionp < 0.05

(%)

RV apex VERBS

NYHA Classp < 0.05

NYH

A C

lass

RV apex VERBS

Documents

Hypertension trials