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

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

VALUE: Secondary Endpoints and Pre-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 Julius S et al. Lancet. June 2004;363.

VALUE: Design Elective titration to target BP (<140/90 mmHg) Month *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 Screening Randomisation End of treatment adjustment period Rollover from previous therapy (92%) *Patient visits every 6 months for months 6–72. Julius S et al. Lancet. June 2004;363.

VALUE: Patient 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 Factor and Disease Algorithm Mann J, Julius S. Blood Press. 1998;7:176–183. Age RangeMale PatientsFemale Patients 50 to 59 yrsAt least 3 risk factors or 1 disease At least 2 risk factors and 1 disease or at least 2 diseases 60 to 69 yrsAt least 2 risk factors or 1 disease ≥70 yrsAt 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 Factors and Diseases Mann J, Julius S. Blood Press. 1998;7:176–183.

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

Valsartan Antihypertensive Long-Term Use Evaluation 15,313 randomised at 942 sites in 31 countries Average follow up 4.2 years Julius S et al. Lancet. June 2004;363.

VALUE: Baseline Characteristics *Mean ± SD or % of total. Variable Valsartan (n = 7649) Amlodipine (n = 7596) Women (%) Age (y) 3240 (42.4%) 67.2 ± 8.2* 3228 (42.5%) 67.3 ± 8.1 BMI (kg/m 2 )28.6 ± ± 5.0 HTN previously treated (%)7088 (92.7%)6989 (92.0%) SBP (mmHg)154.5 ± ± 19.0 DBP (mmHg)87.4 ± ± 10.7 Heart rate (beats/min)72.3 ± ± 10.7 Race (%) Caucasian6821 (89.2%)6796 (89.5%) Black325 (4.3%)314 (4.1%) Oriental272 (3.6%)261 (3.4%) Other231 (3.0%)225 (3.0%) Julius S et al. Lancet. June 2004;363.

*Data are shown as numbers of patients (%) or mean (±SD). Valsartan (n = 7649) Amlodipine (n = 7596) Elevated cholesterol 2555 (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 pattern954 (12.5%)902 (11.9%) Elevated serum creatinine290 (3.8%)260 (3.4%) Julius S et al. Lancet. June 2004;363. VALUE: Qualifying Risk 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 disease3490 (45.6%)3491 (46.0%) Stroke or TIA 1513 (19.8%) 1501 (19.8%) Peripheral arterial disease1052 (13.8%)1062 (14.0%) LVH with strain pattern † 454 (5.9%)462 (6.1%) Julius S et al. Lancet. June 2004;363.

VALUE: Blood Pressure Changes From Baseline to the End of the Study Valsartan- Based Therapy Amlodipine- Based Therapy SBP DBP –20 –15 –10 –5 0 mmHg Julius S et al. Lancet. June 2004;363.

Before Randomisation Study 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% 57% 63% Julius S et al. Lancet. June 2004;363. Non- controlled Controlled Non- controlled Controlled

TrialPublicationBaseline BPFinal BP HOTLancet / / 83 CAPPPLancet / / 90 STOP-2Lancet / / 81 ALLHATJAMA / / 76 NORDILLancet / / 88 INSIGHTLancet / / 82 LIFELancet / / 81 VALUEAm J Hypertens154 / / 79 BP Levels in Other Clinical Trials Adapted from S. Kjeldsen 2000 and updated April 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 Julius S et al. Lancet. June 2004;363. Valsartan (N= 7649) Amlodipine (N = 7596) mmHg Months (or final visit) Sitting SBP by Time and Treatment Group Baseline mmHg Months (or final visit) 5.0 Difference in SBP Between Valsartan and Amlodipine –1.0

VALUE: Diastolic Blood Pressure in Study Julius S et al. Lancet. June 2004;363. Valsartan (N= 7649) Amlodipine (N = 7596) mmHg Months (or final visit) Sitting DBP by Time and Treatment Group mmHg Baseline Months (or final visit) 3.0 Difference in DBP Between Valsartan and Amlodipine –

Favours valsartanFavours amlodipine Hazard Ratio Valsartan/Amlodipine Primary cardiac composite endpoint cardiac mortality cardiac morbidity All myocardial infarction All congestive heart failure All stroke All-cause death New-onset diabetes VALUE: Hazard Ratios for Pre-specified Analyses Julius S et al. Lancet. June 2004;363.

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

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

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

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.

VALUE: Analysis of Results Based on Serial Median Matching 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. Weber MA et al. Lancet. 2004;363:2047–49.

Composite cardiac events Stroke Death Myocardial infarction Heart failure Favours valsartanFavours amlodipine VALUE: Major Study Endpoints in 5006 Patient Pairs (N = 10,012) on Valsartan- or Amlodipine-Based Therapies Using Serial Median Matching Hazard Ratio (95% CI) P 0.90 (0.79–1.03) (0.81–1.28) (0.84–1.10) (0.80–1.19) (0.66–0.99)*0.040 *P < Weber MA et al. Lancet. 2004;363:2047–49.

VALUE: Analysis of Results Based on Serial Median Matching 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: Weber MA et al. Lancet. 2004;363:2047–49.

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

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 ARB Julius S, Kjeldsen SE, Weber M, et al. Lancet 2004;363:

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 control70%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.In meta-analysis 1, β-blockers did not reduce coronary events as well as low-dose diuretics 2.No differences in LIFE trial between ARB (losartan) & β-blocker (atenolol) 2 3.No differences in ALLHAT between chlorthalidone, lisinopril, and amlodipine for primary outcome 4.Taken together, this suggests ARBs and β- blockers may reduce CHD less than thiazide- type diuretics, CCBs, or ACEIs. 1 Psaty BM, Smith ML, Siscovick DS, et al. JAMA 1997;277: Dahlof B, Devereux RB, Kjeldsen SE, et al. Lancet 2002;359: