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DISCLOSURE OF RELATIONSHIPS for William C. Cushman, MD, Over the Past 12 Months

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.

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DISCLOSURE OF RELATIONSHIPS for William C. Cushman, MD, Over the Past 12 Months

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  1. Is It the Achieved Blood Pressure or Specific Medications that Make a Difference in Outcome, or Is the Question Moot? William C. Cushman, MDProfessor, Preventive Medicine and MedicineUniversity of Tennessee College of MedicineChief, Preventive MedicineVA Medical Center, Memphis, Tennessee

  2. 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 DISCLOSURE OF RELATIONSHIPS for William C. Cushman, MD, Over the Past 12 Months

  3. VA Cooperative Morbidity Trial in Hypertension 67% RR 96% RR Stopped after 3.3 yrs Stopped after 1.5 years (N = 380) (N = 143) 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.

  4. Blood Pressure Levels* and Event Reduction in Selected Clinical Trials * 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.

  5. Network Meta-analysis of Antihypertensive Drugs Low-dose Diuretics versus Placebo Outcome RR 95% CI P CHD 0.79 0.69-0.92 0.002 Heart failure 0.51 0.42-0.62 <0.001 Stroke 0.71 0.63-0.81 <0.001 CVD events 0.76 0.69-0.83 <0.001 CVD mortality 0.81 0.73-0.92 0.001 Total mortality 0.90 0.84-0.96 0.002 0.40 0.65 0.90 1.15 1.40 Low-dose diuretics better Low-dose diuretics worse Psaty BM et al. JAMA. 2003;289:2534-2544.

  6. Relative risk of heart failure 1.50 1.25 1.00 0.75 0.50 0.25 -10 -8 -6 -4 -2 0 2 4 BP Reduction and Major Cardiovascular Outcomes 1.50 Relative risk of stroke Stroke CVD Relative risk of CVD 1.25 1.00 0.75 0.50 0.25 Heart Failure CHD Relative risk of CHD -10 -8 -6 -4 -2 0 2 4 Systolic blood pressure difference between randomised groups (mmHg). Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2003;362:1527-1535.

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

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

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

  10. 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.

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

  12. ALLHAT: Doxazosin vs ChlorthalidoneSBP Results by Treatment Group There were no differences in DBP. ALLHAT Collaborative Research group.JAMA. 2000;283:1967-1975

  13. ALLHAT 1.03 (0.92 - 1.15) 1.03 (0.94 - 1.13) 1.07 (0.99 - 1.16) 1.26 (1.10 - 1.46) 1.80 (1.61 - 2.02) 1.20 (1.13 - 1.27) 0.50 1 2 3 Favors Doxazosin Favors Chlorthalidone Final Outcomes Results Doxazosin vs. Chlorthalidone Relative Risk and 95% Confidence Intervals ALLHAT Collaborative Research group.Hypertension. 2003;42:239-246.

  14. 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/b-blocker trials. ALLHAT Collaborative Research group. JAMA. 2000; 283:1967-1975; Hypertension. 2003;42:239-246.

  15. ALLHAT Doxazosin vs Chlorthalidone:Heart Failure, Adjusting* for BP *Adjusted for BL SBP/DBP and FU SBP/DBP †P < 0.001 Davis BR et al. Ann Intern Med. 2002;137:313-320.

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

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

  18. ALLHAT Major Outcomes Relative Risks and 95% Confidence Intervals Amlodipine/Chlorthalidone Lisinopril/Chlorthalidone CHD 0.99 (0.91-1.08) 0.98 (0.90-1.07) All-Cause Mortality 1.00 (0.94-1.08) 0.96 (0.89-1.02) Stroke 1.15 (1.02-1.30) 0.93 (0.82-1.06) Combined CVD 1.10 (1.05-1.16) 1.04 (0.99-1.09) 1.19 (1.07-1.31) Heart Failure 1.38 (1.25-1.52) ESRD 1.11 (0.88-1.38) 1.12 (0.89-1.40) 0.50 1 2 0.50 1 2 Favors Favors Lisinopril Chlorthalidone Favors Favors Amlodipine Chlorthalidone ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.

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

  20. ALLHAT Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group for Year 1 .02 Amlodipine Lisinopril Cumulative HF Rate .01 Chlorthalidone 0 0 .5 1 Years to HF Davis, et al. Circulation. 2006;113:2201-2210.

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

  22. 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* RR L/C = 0.92 RR L/C = 1.01 ≥ RR = hazard ratio *p<0.01 ALLHAT. Unpublished data. 2006.

  23. ALLHAT BP Differences: Lisinopril versus Chlorthalidone • 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. • Stroke (1.15 → 1.12) & HF (1.20 → 1.17), overall • Stroke (1.40 → 1.35) & HF (1.32 → 1.26), for Blacks ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.

  24. ALLHAT BP Differences: Lisinopril versus Chlorthalidone(continued) • 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. ALLHAT Collaborative Research group JAMA. 2002; 288: 2981-2997.

  25. Cardiovascular Events and Total Mortality in SCOPE and LIFE Relative risk 0.5 1.0 2.0 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 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 AT1 blockade Favors control LIFE (n=9193): losartan vs atenolol SCOPE (n=4964): candesartan vs placebo Lithel H et al. J Hypertens. 2003;21:875–886.

  26. Initial Combinations of Medications for Management of Hypertension* Diuretics ACE inhibitors or ARBs Calciumantagonists * Compelling indications may modify this.

  27. 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.

  28. Achieved Blood Pressure Versus Specific Medications: Effects on Outcomes(continued) • 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.

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