attention the slides in this set which contain the value study logo are unedited slides from the...

ATTENTION

The slides in this set which contain the VALUE study logo are unedited slides from the VALUE study / investigators.

There are additional notes on slides #16, 23 in addition to those from VALUE.

The rest of the slides are ALLHAT investigators’ slides and not approved by the VALUE investigators.

In hypertensive patients at high cardiovascular risk, for the same level of blood pressure control, valsartan will be more effective than amlodipine in reducing cardiac morbidity and mortality

VALUE: Primary HypothesisVALUE: Primary Hypothesis

Julius S et al. Lancet. June 2004;363.

VALUE: Primary EndpointVALUE: Primary Endpoint

• Composite cardiac morbidity and mortality

– sudden cardiac death

– fatal/nonfatal MI

– evidence of recent MI on autopsy

– emergency thrombolytic/fibrinolytic treatment and/or emergency PTCA/CABG to avoid MI

– death during/after PTCA/CABG

– new or chronic CHF requiring hospital management

– heart failure deathMann J, Julius S. Blood Press. 1998;7:176–183.

VALUE: Secondary Endpoints and VALUE: Secondary Endpoints and Pre-specified AnalysesPre-specified Analyses

• Secondary Endpoints:– fatal/non-fatal myocardial infarction

– fatal/non-fatal stroke

– fatal/non-fatal heart failure

• Pre-specified Analyses:– all-cause mortality

– new-onset diabetes


VALUE: DesignElective titration to target BP (<140/90 mmHg)

Month 0.5 0 1 2 3 4 6 * 72

A 10 mg +HCTZ 25 mg

A 5 mg

A 10 mg +HCTZ 12.5 mg

A 10 mg

V 80 mg

V 160 mg

V 160 mg +HCTZ 12.5 mg

V 160 mg +HCTZ 25 mg

Amlodipine-based regimen

V 160 mg +HCTZ 25 mg + "Free" add-

on

A 10 mg +HCTZ 25 mg + "Free" add-

on

Valsartan-based regimen

ScreeningRandomisation End of treatment adjustment

period

Rolloverfromprevious therapy(92%)

*Patient visits every 6 months for months 6–72.Julius S et al. Lancet. June 2004;363.

VALUE:VALUE: Patient PopulationPatient Population

• Treated or untreated hypertensive patients

– entry criteria for untreated hypertension:160–210 mmHg systolic, 95–105 mmHg diastolic

• Age ≥50 years, male or female

• High-risk for cardiac events

– one or more defined risk factors or diseases

Mann J, Julius S. Blood Press. 1998;7:176–183.

VALUE: Qualifying Risk FactorVALUE: Qualifying Risk Factorand Disease Algorithmand Disease Algorithm


Age Range Male Patients Female Patients

50 to 59 yrs At least 3 risk factors or 1

disease

At least 2 risk factors and 1

disease or at least 2 diseases

60 to 69 yrs At least 2 risk factors or 1

disease

At least 2 risk factors

or 1 disease

≥70 yrs At least 1 risk factor or 1 disease

At least 1 risk factor

or 1 disease

Risk Factors• Diabetes mellitus

• Cigarette smoking

• Hypercholesterolemia

• Left ventricular hyper-trophy (LVH) without strain patterns

• Proteinuria• Serum creatinine 150–265 µmol/L

Diseases• History of CHD

• Peripheral vascular disease

• Stroke or transient ischemic attack

• LVH with ECG documented strain patterns (ST segment depression)

VALUE: Qualifying Risk FactorsVALUE: Qualifying Risk Factorsand Diseasesand Diseases


VALUE:VALUE: Exclusion CriteriaExclusion Criteria

• Renal artery stenosis

• Pregnancy

• Acute myocardial infarction

• Percutaneous transluminal coronary angioplasty, or coronary artery bypass graft within the past 3 months

• Clinically relevant valvular disease

• Cerebrovascular accident in the past 3 months

• Severe hepatic disease

• Severe chronic renal failure (defined as creatinine >265 mol/L)

• Congestive heart failure requiring ACE inhibitor therapy

• Patients on monotherapy with beta blockers for both coronary artery disease and hypertension


VValsartan alsartan AAntihypertensive ntihypertensive LLong-Term ong-Term UUse se EEvaluationvaluation15,313 randomised at 942 sites in 31 countries

Average follow up 4.2 years


VALUE: Baseline CharacteristicsVALUE: Baseline Characteristics

*Mean ± SD or % of total.

VariableValsartan

(n = 7649)Amlodipine(n = 7596)

Women (%)Age (y)

3240 (42.4%)67.2 ± 8.2*

3228 (42.5%)67.3 ± 8.1

BMI (kg/m2) 28.6 ± 5.1 28.7 ± 5.0HTN previously treated (%) 7088 (92.7%) 6989 (92.0%)SBP (mmHg) 154.5 ± 19.0 154.8 ± 19.0DBP (mmHg) 87.4 ± 10.9 87.6 ± 10.7Heart rate (beats/min) 72.3 ± 10.8 72.5 ± 10.7

Race (%) Caucasian 6821 (89.2%) 6796 (89.5%) Black 325 (4.3%) 314 (4.1%) Oriental 272 (3.6%) 261 (3.4%) Other 231 (3.0%) 225 (3.0%)


*Data are shown as numbers of patients (%) or mean (±SD).

Valsartan (n = 7649)

Amlodipine (n = 7596)

Elevated cholesterol2555 (33.4%)

2522 (33.2%)

Diabetes mellitus2395

(31.3%) 2428 (31.9%)

Current smoking1826

(23.9%) 1838 (24.2%)

Proteinuria1721

(22.5%) 1714 (22.6%)

LVH without strain pattern 954 (12.5%) 902 (11.9%)

Elevated serum creatinine 290 (3.8%) 260 (3.4%)


VALUE: Qualifying Risk Factors*VALUE: Qualifying Risk Factors*

VALUE: Qualifying Disease Factors*VALUE: Qualifying Disease Factors*

*Data are shown as numbers of patients (%) or mean (±SD). †LVH including left bundle branch block.

Valsartan (n = 7649)

Amlodipine (n = 7596)

Coronary heart disease 3490 (45.6%) 3491 (46.0%)

Stroke or TIA 1513 (19.8%)

1501 (19.8%)

Peripheral arterial disease 1052 (13.8%) 1062 (14.0%)

LVH with strain pattern† 454 (5.9%) 462 (6.1%)


VALUE: Blood Pressure Changes From Baseline to the End of the

Study

Valsartan-Based

Therapy

Amlodipine-Based Therapy

SBPDBP

–20

–15

–10

–5

0

mm

Hg


Before Randomisatio

nStudy End

Valsartan-Based

Regimen

Amlodipine-Based Regimen

VALUE: Trends in SBP Control (<140 mmHg)

92% of patients were previously treated with antihypertensive medication(s) at time of entry.

22%22%

22%22%

57%57%

63%63%


Non-controlled

Controlled

Non-controlled

Controlled

Trial Publication Baseline BP Final BP

HOT Lancet 1998 175 / 105 142 / 83CAPPP Lancet 1999 161 / 99 150 / 90STOP-2 Lancet 1999 194 / 98 159 / 81ALLHAT JAMA 2000 145 / 83 136 / 76NORDIL Lancet 2000 173 / 106 151 / 88INSIGHT Lancet 2000 173 / 99 138 / 82LIFE Lancet 2002 174 / 98 145 / 81VALUE Am J Hypertens 154 / 88 138 / 79

BP Levels in Other Clinical Trials BP Levels in Other Clinical Trials

Adapted from S. Kjeldsen 2000 and updated April 2002.

William C. Cushman, MD:

The ALLHAT data is not what we want to promote, since it is apparently from the doxazosin paper – we should add a slide after this giving our “final BP” (end of study) to be comparable to VALUE end of study BP. Charlie has data. Also, in notes, it doesn’t compare BP control rates to ALLHAT.

William C. Cushman, MD:

The ALLHAT data is not what we want to promote, since it is apparently from the doxazosin paper – we should add a slide after this giving our “final BP” (end of study) to be comparable to VALUE end of study BP. Charlie has data. Also, in notes, it doesn’t compare BP control rates to ALLHAT.

VALUE: Systolic Blood Pressure in Study


Valsartan (N= 7649)

Amlodipine (N = 7596)

135

140

145

150

155

mm

Hg

Months (or final visit)

Sitting SBP by Time and Treatment Group

Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66

01.02.03.04.0

1 24 48

mm

Hg

2 3 4 6 12 18 30 36 42 54 60 66Months (or final visit)

5.0Difference in SBP Between Valsartan and Amlodipine

–1.0

VALUE: Diastolic Blood Pressure in Study


Valsartan (N= 7649)

Amlodipine (N = 7596)

mm

Hg

Months (or final visit)

Sitting DBP by Time and Treatment Group

mm

Hg

Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66

75

85

80

90

0

1.02.0

1 24 482 3 4 6 12 18 30 36 42 54 60 66

Months(or final visit)

3.0

Difference in DBP Between Valsartan and Amlodipine

–1.0

4.0

5.0

Favours valsartan Favours amlodipine

Hazard RatioValsartan/Amlodipine

Primary cardiac composite endpoint

cardiac mortality

cardiac morbidity

All myocardial infarction

All congestive heart failure

All stroke

All-cause death

New-onset diabetes

0.5 1 2

VALUE: Hazard Ratios for Pre-specified Analyses


VALUE: Main Results

Good BP control was achieved with both treatment regimens, but BP decrease in the amlodipine group was more pronounced, particularly early in the trial

Despite BP differences, the primary composite cardiac endpoint in both groups was not different


VALUE: Other Results

• Incidence of stroke was lower, but not significantly, in the amlodipine group

• Incidence of non-fatal MI was significantly lower in the amlodipine group

• There was a positive trend in favour of valsartan for less heart failure but this did not reach significance

• There was a highly significant lower rate of new-onset diabetes in the valsartan group


• The observed difference in stroke rates appears to be strongly related to differences in achieved BPs

• The benefits of valsartan in heart failure prevention emerged later in the study when BP differences were smaller, indicating that there is a potential beneficial effect of valsartan beyond BP control

VALUE: Interpretations


VALUE: Analysis of Results Based on Serial Median Matching

Rationale:

Differences in achieved BP levels in VALUE precluded valid comparisons of drug effects on outcomes. Therefore, a statistical technique that adjusts for BP differences was applied post hoc to create treatment cohorts with closely similar characteristics

Weber MA et al. Lancet. 2004;363:2047–49.


Description:

The novel computerised procedure of Serial Median Matching was applied at 6 months, following the treatment adjustments intended to achieve BP control.

The programme selected the most median patient (by achieved systolic BP) in the valsartan group; this patient was paired with one from the amlodipine group ( 2 mmHg) and was matched also for age, sex and the presence or absence of prior coronary disease, stroke and diabetes.

The newly created patient pair was moved to a new database, and the procedure repeated serially until all possible patient pairs were matched.


Composite cardiac events

Stroke

Death

Myocardial infarction

Heart failure

0.6 0.8 1.0 1.2 1.4

Favours valsartan Favours amlodipine

VALUE: Major Study Endpoints in 5006 Patient VALUE: Major Study Endpoints in 5006 Patient Pairs (N = 10,012) on Valsartan- or Amlodipine-Pairs (N = 10,012) on Valsartan- or Amlodipine-Based Therapies Using Serial Median MatchingBased Therapies Using Serial Median Matching

Hazard Ratio (95% CI) P

0.90 (0.79–1.03) 0.111

1.02 (0.81–1.28) 0.899

0.96 (0.84–1.10) 0.566

0.97 (0.80–1.19) 0.791

0.81 (0.66–0.99)* 0.040

*P < 0.05.



Serial median matching created valsartan-amlodipine patient pairs matched exactly for systolic BP and demographic and clinical characteristics excluding the high and low extremes of achieved BPs.

It allowed us to address the original study hypothesis, and demonstrated that for the same achieved BPs, valsartan in an intermediate dose had effects similar to amlodipine on most CV endpoints, and was more effective in reducing heart failure hospitalisations.

Conclusions:


VALUE: Analyses of Results Based on BP Control

Blood pressure control, and rapidity of response, are critical for reducing events in high-risk hypertension

The significant between-group differences in heart failure and diabetes suggest that valsartan may offer benefits beyond BP control

Overall Conclusions:


VALUE Summary

• ARB (valsartan) not more effective than CCB (amlodipine) in decreasing cardiac mortality and morbidity– CCB →lower SBP than ARB (4 mm Hg at 1-2

months, 2 mm Hg at 6 months)

– CCB →significantly lower incidence of MI, higher incidence of new-onset diabetes

• Serial median matching adjusted for BP Δ– MI incidence became equivalent for CCB & ARB

– Lower rate of HF with ARBJulius S, Kjeldsen SE, Weber M, et al. Lancet 2004;363:2022-31

Comments on VALUE Analyses

• Differing odds ratios over time

– Cox regressions assume constant hazard ratios, but were used in analyses anyway

• Rationale for BP adjustment method?

– Discards thousands of observations.

– Alternatives: Cox model with BP as time-dependent covariate or beginning at 6 months

Does Lower Rate of BP Control with ARB Imply Differences should be Dismissed?

• If a drug does not reduce CVD more because of less effect on BP, seems like limiting property of drug

• RAS-blocker did not have sufficient special properties to overcome 2 mm Hg SBP disadvantage

• In VALUE, thiazide available for step-up – 25% of both groups – but did not obviate BP disadvantage for RAS-blocker

ALLHAT diuretic

VALUE – valsartan

ALLHAT – amlodipine

VALUE - amlodipine

BP control 70% 56% 68% 62%

Diabetes Incidence

If CCBs raise incidence of new-onset diabetes but lower incidence of MI compared with ARBs, why would an ARB be preferred?

ARBs & β-blockers may prevent MI less than thiazide-like diuretics, CCBs, ARBs

1.1. In meta-analysisIn meta-analysis11, , ββ-blockers did not reduce -blockers did not reduce coronary events as well as low-dose diureticscoronary events as well as low-dose diuretics

2.2. No differences in LIFE trial between ARB (losartan) No differences in LIFE trial between ARB (losartan) & & ββ-blocker (atenolol)-blocker (atenolol)22

3.3. No differences in ALLHAT between chlorthalidone, No differences in ALLHAT between chlorthalidone, lisinopril, and amlodipine for primary outcomelisinopril, and amlodipine for primary outcome

4.4. Taken together, this suggests ARBs and Taken together, this suggests ARBs and ββ-blockers -blockers may reduce CHD less than thiazide-type diuretics, may reduce CHD less than thiazide-type diuretics, CCBs, or ACEIs.CCBs, or ACEIs.

1Psaty BM, Smith ML, Siscovick DS, et al. JAMA 1997;277:739-745.2Dahlof B, Devereux RB, Kjeldsen SE, et al. Lancet 2002;359:995-1003.

attention the slides in this set which contain the value study logo are unedited slides from the...

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