2. Is It the Achieved Blood Pressure or Specific Medications that Make a Difference in Outcome, or Is the Question Moot? William C. Cushman, MD Professor, Preventive Medicine and Medicine University of Tennessee College of Medicine Chief, Preventive Medicine VA Medical Center, Memphis, Tennessee

3. 3 DISCLOSURE OF RELATIONSHIPS for William C. Cushman, MD, Over the Past 12 Months Type of Relationship Name of Company Grant/Research Support Astra-Zeneca, Abbott, Novartis, Aventis, King Pharmaceuticals Consultant Sanofi-Aventis, Bristol-Myers Squibb, Novartis, Pfizer, Sankyo, Forest, Myogen Speakers Bureau none Major Stock Shareholder none Other Support, Tangible or Intangible none

4. VA Cooperative Morbidity Trial in Hypertension Stopped after 1.5 years Stopped after 3.3 yrs 96% RR 67% RR Blood pressure (BP) goal: DBP <90 mm Hg. Therapy: HCTZ + reserpine + hydralazine. NNT = 2.7 for both. RR = risk reduction. JAMA. 1967;202(11):1028-1034. JAMA. 1970;213(7): 1143-1152. (N = 143) (N = 380)

5. Blood Pressure Levels* and Event Reduction in Selected Clinical Trials Trial Baseline BP Treated BP Event ↓ ActiveControl HDFP159/101131/86142/91 17% - mortality SHEP170/77144/68155/73 36% - stroke Syst-EUR174/86151/79161/84 42% - stroke PROGRESS147/86134/78143/82 28% - stroke PROGRESS - HTN 159/93138/81146/84 32% - stroke HOPE139/79135/76138/78 22% - CVD * mm Hg Hypertension Detection and Follow-up Program (HDFP). JAMA. 1979;242(23):2562-2571. Systolic Hypertension in the Elderly Program (SHEP) Cooperative Research Group. JAMA. 1991;265(24):3255-3264. Systolic Hypertension in Europe Trial (Syst-EUR) Investigators. Lancet. 1997;350:757-764. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Collaborative Group. Lancet. 2001;358(9287):1033-1041. Heart Outcomes Prevention Valuation Study (HOPE) Investigators. N Engl J Med. 2000;342:145-153.

6. Low-dose Diuretics versus Placebo CHD0.790.69-0.920.002 Heart failure0.510.42-0.62<0.001 Stroke0.710.63-0.81<0.001 CVD events0.760.69-0.83<0.001 CVD mortality0.810.73-0.920.001 Total mortality0.900.84-0.960.002 OutcomeRR95% CIP 0.400.650.901.151.40 Low-dose diuretics better Low-dose diuretics worse Network Meta-analysis of Antihypertensive Drugs Psaty BM et al. JAMA. 2003;289:2534-2544.

7. Systolic blood pressure difference between randomised groups (mmHg). Relative risk of stroke Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535. Relative risk of CVD 0.25 0.50 0.75 1.00 1.25 1.50 Relative risk of heart failure 0.25 0.50 0.75 1.00 1.25 1.50 -10-8-6-4-2024 BP Reduction and Major Cardiovascular Outcomes -10-8-6-4-2024 Relative risk of CHD Stroke CHD Heart Failure CVD

8. MRC in the Elderly: Mean Level of BP by Sex and Treatment Mean systolic BP Mean diastolic BP MenWomen Placebo  -blocker Diuretic MRC Working Party. BMJ. 1992;304:405-412. Interval from entry (months)

9. MRC in the Elderly: Effects of Treatment on Stroke Incidence Cumulative % events Interval from entry (years) Treatment vs Placebo, P = 0.04 (RR = 25%) N = 4396 MRC Working Party. BMJ. 1992;304:405-412. Diuretic vs β-blocker, P = 0.33 Placebo  -blocker Diuretic

10. MRC in the Elderly: Effects of Treatment on Coronary Events Cumulative % events Interval from entry (years) Treatment vs Placebo, P = 0.08 (RR = 19%) Diuretic vs β-blocker, P = 0.006 N = 4396 Placebo  -blocker Diuretic MRC Working Party. BMJ. 1992;304:405-412.

11. MRC in the Elderly: Effects of Treatment on Cardiovascular Events Diuretic vs β-blocker, P = 0.007 N = 4396 MRC Working Party. BMJ. 1992;304:405-412.

12. 12 90% previously treated 10% untreated 42,418 high-risk hypertensive patients Chlorthalidone 12.5-25 mg Amlodipine 2.5-10 mg Lisinopril 10-40 mg Doxazosin 1-8 mg N=15,255 N=9,048 N=9,054 N=9,061 Atenolol 28.0% Clonidine 10.6% Reserpine 4.3% Hydralazine 10.9% Hypertension Trial ALLHAT STEP 2 AND 3 AGENTS STEP 1 AGENTS (Double-blind)

13. 13 ALLHAT: Doxazosin vs Chlorthalidone SBP Results by Treatment Group There were no differences in DBP. ALLHAT Collaborative Research group. JAMA. 2000;283:1967-1975BL6M1Y2Y4YDOX146.3141.1140.1138.2137.4 CTD146.2138.2136.9135.9135.3

14. Relative Risk and 95% Confidence Intervals Final Outcomes Results Doxazosin vs. Chlorthalidone Favors Doxazosin Favors Chlorthalidone 0.50123 CHD All-Cause Mortality Combined CHD Stroke, p=0.001 Heart Failure, p<0.001 Combined CVD, p<0.001 1.20 (1.13 - 1.27) 1.80 (1.61 - 2.02) 1.26 (1.10 - 1.46) 1.07 (0.99 - 1.16) 1.03 (0.94 - 1.13) 1.03 (0.92 - 1.15) ALLHAT Collaborative Research group. Hypertension. 2003;42:239-246. ALLHAT

15. 15 Estimated BP Effect on RR Differences A 3 mm Hg higher SBP in the doxazosin group could explain a 10% to 20% difference in HF* but not an 80% difference in risk. 3 mm Hg could account for 15-20% increase in stroke risk**—26% was observed. Thus, the observed BP differential may explain much of the stroke, but not HF, differences observed between chlorthalidone and doxazosin in ALLHAT. * Based on SHEP and Syst-EUR. ** Based on meta-analysis of all diuretic/  -blocker trials. ALLHAT Collaborative Research group. JAMA. 2000; 283:1967-1975; Hypertension. 2003;42:239-246.

16. 16 Doxazosin vs Chlorthalidone: Doxazosin vs Chlorthalidone: Heart Failure, Adjusting* for BP ALLHAT ALL HF ALL HF RR (95% CI) Hosp./Fatal HF RR (95% CI) RR (95% CI) As randomized 2.04 † (1.79, 2.32) 1.83 † (1.58, 2.13) Adjusted 2.00 † (1.72, 2.32) 1.80 † (1.51, 2.13) *Adjusted for BL SBP/DBP and FU SBP/DBP Davis BR et al. Ann Intern Med. 2002;137:313-320. † P < 0.001

17. 17 Doxazosin vs Chlorthalidone: Heart Failure Beyond 1 Yr by BP Level at 1 Yr RR=1.17 RR=1.63* Davis BR et al. Ann Intern Med. 2002;137:313-320. RR = hazard ratio (doxazosin/chlorthalidone) *CI = 1.20-2.05 ≥

18. 18 BP Levels by Treatment Group for Chlorthalidone, Amlodipine, and Lisinopril BP <140/90 mm Hg at 5 yrs: Chlorthalidone 68% Amlodipine 66% Lisinopril 61% ALLHAT Collaborative Research group JAMA. 2002;288:2981-2997. 2 mm Hg lower in ~2 mm Hg lower in chlorthalidone vs lisinopril group ~1 mm Hg lower in amlodipine group

19. 19 Major Outcomes Relative Risks and 95% Confidence Intervals Amlodipine/Chlorthalidone 0.5012 ESRD 1.12 (0.89-1.40) Heart Failure 1.38 (1.25-1.52) Combined CVD 1.04 (0.99-1.09) Stroke 0.93 (0.82-1.06) All-Cause Mortality 0.96 (0.89-1.02) CHD 0.98 (0.90-1.07) Favors Amlodipine Chlorthalidone Lisinopril/Chlorthalidone 0.5012 1.11 (0.88-1.38) 1.19 (1.07-1.31) 1.10 (1.05-1.16) 1.15 (1.02-1.30) 1.00 (0.94-1.08) 0.99 (0.91-1.08) Favors Lisinopril Chlorthalidone ALLHAT ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.

20. 1.29 (0.94 - 1.75) ESRD 1.32 (1.11 - 1.58) Heart Failure 1.40 (1.17 - 1.68) Stroke* 1.19 (1.09 - 1.30) Combined CVD* 1.06 (0.95 - 1.18) All-Cause Mortality 1.10 (0.94 - 1.28) CHD Favors Favors Lisinopril Chlorthalidone 0.5012 0.93 (0.67 - 1.30) 1.15 (1.01 - 1.30) 1.00 (0.85 - 1.17) 1.06 (1.00 - 1.13) 0.97 (0.89 - 1.06) 0.94 (0.85 - 1.05) 0.50 1 2 Only Subgroup Differences: Lisinopril vs Chlorthalidone in Blacks/Non-Blacks for CVD & Stroke Blacks Non-Blacks ALLHAT Favors Favors Lisinopril Chlorthalidone Wright JT et al. JAMA. 2005; 293: 1595-1608. * Significant interaction

21. 21 Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group for Year 1 ALLHAT Cumulative HF Rate Years to HF 0.51 0.01.02 Chlorthalidone Amlodipine Lisinopril RR (95% CI) P value A/C 2.32 (1.83-2.94) <.001 L/C 2.22 (1.75-2.82) <.001 Davis, et al. Circulation. 2006;113:2201-2210.

22. 22 Heart Failure Beyond 1 Yr by BP Level at 1 Yr in Chlorthalidone, Amlodipine and Lisinopril Groups RR U/C = 1.41* ALLHAT. Unpublished data. 2006. ≥ RR U/C = hazard ratio uncontrolled/controlled *p<0.001, **p=0.017, † p=0.023 RR U/C = 1.29 † RR U/C = 1.27**

23. 23 Amlodipine and Lisinopril vs Chlorthalidone: Heart Failure Beyond 1 Yr by BP Level at 1 Yr RR A/C = 1.16 RR A/C = 1.30* ALLHAT. Unpublished data. 2006. ≥ RR = hazard ratio *p<0.01 RR L/C = 0.92 RR L/C = 1.01

24. 24 BP Differences: Lisinopril versus Chlorthalidone Mean follow-up SBP for L versus C Mean follow-up SBP for L versus C  2 mm Hg higher—all participants  4 mm Hg higher—Black participants Adjustment for follow-up SBP/DBP as time- dependent covariates in a Cox regression model slightly reduced the relative risks, but they remained statistically significant. Adjustment for follow-up SBP/DBP as time- dependent covariates in a Cox regression model slightly reduced the relative risks, but they remained statistically significant.  Stroke (1.15 → 1.12) & HF (1.20 → 1.17), overall  Stroke (1.40 → 1.35) & HF (1.32 → 1.26), for Blacks ALLHAT ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.

25. 25 Prospective observational studies predict that 2 mm Hg difference → 9% higher stroke mortality and 6% higher HF mortality, versus 15 and 19% higher risk (fatal + nonfatal events) observed in ALLHAT. Prospective observational studies predict that 2 mm Hg difference → 9% higher stroke mortality and 6% higher HF mortality, versus 15 and 19% higher risk (fatal + nonfatal events) observed in ALLHAT. Based on same data, 4 mm Hg difference in blacks would predict 19% higher stroke mortality and 14% higher HF mortality, versus 40% and 32% higher risk (fatal + nonfatal events) observed in ALLHAT. Based on same data, 4 mm Hg difference in blacks would predict 19% higher stroke mortality and 14% higher HF mortality, versus 40% and 32% higher risk (fatal + nonfatal events) observed in ALLHAT. BP Differences: Lisinopril versus Chlorthalidone (continued) ALLHAT ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.

26. 26 0.5 1.0 2.0 Cardiovascular Events and Total Mortality in SCOPE and LIFE Lithel H et al. J Hypertens. 2003;21:875–886. Relative risk Major CV event SCOPE LIFE CV death SCOPE LIFE Fatal/non-fatal stroke SCOPE LIFE Fatal/non-fatal MI SCOPE LIFE Total Mortality SCOPE LIFE Favors AT 1 blockade Favors control There was little BP difference in LIFE and 3.2/1.6 mm Hg lower BP in the candesartan group in SCOPE, but event RRs were similar LIFE (n=9193): losartan vs atenolol SCOPE (n=4964): candesartan vs placebo

27. Initial Combinations of Medications for Management of Hypertension* Diuretics ACE inhibitors orARBs Calcium antagonists * Compelling indications may modify this.

28. Achieved Blood Pressure Versus Specific Medications: Effects on Outcomes Drugs with very different physiologic effects may logically have different effects on organs/events independent of BP. In ALLHAT and other trials, adjustment of clinical event rates based on observational analyses of BP differences are limited by variability of BP measurement and absence of non-clinic BPs.

29. Outcome differences in many studies are not fully explained by clinically detectable BP differences. BP control IS of paramount importance, but it DOES also matter which drugs we use. Achieved Blood Pressure Versus Specific Medications: Effects on Outcomes (continued)