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Hypertension in the Elderly and Additional Data from the ALLHAT Study

Hypertension in the Elderly and Additional Data from the ALLHAT Study. William C. Cushman, MD, FACP. Professor, Preventive Medicine and Medicine University of Tennessee Health Science Center Chief, Preventive Medicine VA Medical Center, Memphis Memphis, Tennessee.

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Hypertension in the Elderly and Additional Data from the ALLHAT Study

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  1. Hypertension in the Elderly and Additional Data from the ALLHAT Study William C. Cushman, MD, FACP Professor, Preventive Medicine and MedicineUniversity of TennesseeHealth Science Center Chief, Preventive MedicineVA Medical Center, Memphis Memphis, Tennessee

  2. Hypertension Affects Approximately 65 Million Americans: 28% of Adults Population With Hypertension (%) Hypertension. October 2004;44:1-7

  3. Arterial Wall Compliance and Pulse Pressure Wave Elastic Vessel Stiff Vessel Systole Diastole Systole Diastole Stroke Volume Aorta Resistance Arterioles Pressure (Flow) Young Artery Arteriosclerotic Artery Bentley Dw, Izzo JL. J Am Geriatr Soc. 1982; 30:352-359.

  4. Non-Hispanic Black Non-Hispanic White Mexican American SBP (mm Hg) SBP (mm Hg) SBP (mm Hg) SBP (mm Hg) DBP (mm Hg) DBP (mm Hg) DBP (mm Hg) DBP (mm Hg) 150 150 150 150 130 130 130 130 110 110 110 110 80 80 80 80 70 70 70 70 0 0 0 0 18-29 18-29 30-39 30-39 40-49 40-49 50-59 50-59 60-69 60-69 70-79 70-79 80+ 80+ Mean Systolic and Diastolic BP by Age and Race/Ethnicity for Men and Women (US Population Age 18 Years, NHANES III) Pulse pressure Pulse pressure Men, Age (y) Women, Age (y) Burt VI, et al. Hypertension. 1995;25:305-313.

  5. Distribution of Untreated Hypertensive Individuals by Age and Hypertension Subtype (NHANES III) 17% 20% 16% 16% 20% 11% ISH SDH IDH #s at the tops of bars represent the overall % distribution of all subtypes of untreated HTN in age group. ISH = isolated systolic HTN, SDH = systolic-diastolic HTN, IDH = isolated diastolic HTN. Franklin, et al. Hypertension 2001;37:869-74

  6. Prevalence of High BP in Americans Aged 20 Years and Older by Age and Gender (NHANES IV: 1999-2000)

  7. Ischemic Heart Disease Mortality Rate in Each Decade of Age SBP DBP Age at risk: 256 256 80-89 y 128 128 70-79 y 64 64 60-69 y 32 32 IHDmortality (floating absolute risk and 95% CI) 50-59 y 16 16 40-49 y 8 8 4 4 2 2 1 1 120 140 160 180 70 80 90 100 110 Usual SBP (mm Hg) Usual DBP (mm Hg) IHD, ischemic heart disease. Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

  8. Stroke Mortality in Each Decade of Age SBP DBP Age at risk: 256 256 80-89 y 128 128 70-79 y 64 64 60-69 y 32 32 Stroke mortality (floating absolute risk and 95% CI) 50-59 y 16 16 8 8 4 4 2 2 1 1 120 140 160 180 70 80 90 100 110 Usual SBP (mm Hg) Usual DBP (mm Hg) Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

  9. Diuretics or B-Blockers as Initial Therapy in 8 Randomized Controlled Hypertension Treatment Trials in Older Persons Risk Reduction (%) All reductions significant (p <.05) except CHD and death with B-blockers Cutler JA, et al. In Laragh JH, Brenner BM, eds, Hypertension 1995

  10. ISH: META-ANALYSIS OF OUTCOME TRIALS n=15,693—3.8-yr follow-up 1000 Nonfatal events Fatal events Treatment Control 835 800 734 T 656 647 600 C Total individuals affected (n) 387 373 342 400 327 293 279 100 329 200 244 193 136 100 0 T C T C T C T C T C Stroke30%<0.0001 CHD23%<0.001 AllCV events 26%<0.001 Totalmortality13%0.002 Non-CVmortality % odds reduction 2P value Adapted from Staessen et al. Lancet 2000;355:865

  11. Meta-analysis of Hypertension Treatment Trials in People > 80 Years of Age 6 p=ns -22 p=ns -34 -39 p=.014 p=.01 Lancet 1999;353:793-796

  12. Treatment Recommendations for the Elderly in JNC 7 Recommendations are no different according to age for: • BP classification • BP goals • Lifestyle interventions • Selection of medications

  13. Lifestyle Modifications

  14. Without Compelling Indications With Compelling Indications Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist. Algorithm for Treatment of Hypertension Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices

  15. 0.40 0.65 0.90 1.15 1.40 Low-dose diuretics better Low-dose diuretics worse 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 Psaty, et al. JAMA 2003; 289:2534

  16. Hypertension Treatment by Drug Class Diuretics ß-Blocker ACE Inhibitors CCBs ARBs IMS Health NDTI, 1978-2002

  17. 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%

  18. ALLHAT BP Results by Treatment Group BP <140/90 mm Hg @ 5 yrs: Chlorthalidone 68% (66% overall) Amlodipine 66% Lisinopril 61%

  19. ALLHATCumulative Percent Controlled (BP <140/90 mm Hg) at Five Years Derived from Cushman et al. J Clin Hypertens. 2002;4:393-404.

  20. ALLHAT Major Outcomes Relative Risks and 95% Confidence Intervals Amlodipine/Chlorthalidone Lisinopril/Chlorthalidone CHD 0.98 (0.90-1.07) 0.99 (0.91-1.08) All-Cause Mortality 0.96 (0.89-1.02) 1.00 (0.94-1.08) Stroke 0.93 (0.82-1.06) 1.15 (1.02-1.30) Combined CVD 1.04 (0.99-1.09) 1.10 (1.05-1.16) Heart Failure 1.38 (1.25-1.52) 1.19 (1.07-1.31) 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

  21. ALLHAT Blood Pressure at 5 Yearsby Race * P < 0.005 05/15/03

  22. ALLHAT Only Subgroup Differences:Lisinopril vs Chlorthalidone in Blacks/Non-Blacks for CVD & Stroke Non-Blacks Blacks CHD 1.10 (0.94 - 1.28) 0.94 (0.85 - 1.05) All-Cause Mortality 1.06 (0.95 - 1.18) 0.97 (0.89 - 1.06) Combined CVD 1.19 (1.09 - 1.30) 1.06 (1.00 - 1.13) Stroke 1.40 (1.17 - 1.68) 1.00 (0.85 - 1.17) Heart Failure 1.32 (1.11 - 1.58) 1.15 (1.01 - 1.30) ESRD 1.29 (0.94 - 1.75) 0.93 (0.67 - 1.30) 0.50 1 2 0.50 1 2 Favors Favors Lisinopril Chlorthalidone Favors Favors Lisinopril Chlorthalidone

  23. ALLHAT .15 .12 .09 Cumulative HF Rate .06 .03 0 0 1 2 3 4 5 6 7 Years to HF Cumulative Event Rates for Heart Failure by Treatment Group Amlodipine Lisinopril Number at risk: Amlodipine 9,048 8,535 8,185 7,801 6,785 3,775 1,780 210 9,054 8,496 8,096 7,689 6,698 3,789 1,837 313 Lisinopril

  24. ALLHAT .15 .12 .09 Cumulative CHF Rate .06 .03 0 0 1 2 3 4 5 6 7 Years to HF Heart Failure by Treatment Group Chlorthalidone Amlodipine Lisinopril

  25. 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

  26. ALLHAT All Cause Mortality .7 .6 From 1st HF Event .5 .4 Cumulative Mortality Rate .3 From Baseline .2 .1 0 0 1 2 3 4 5 6 Years to Death

  27. ALLHAT Validity of HF Diagnosis • 3031 cases centrally reviewed • Criteria – ALLHAT, Framingham, reviewer judgment • 70-84% confirmed on central review • Similar across treatment group • Treatment group effects larger in confirmed cases

  28. ALLHAT Biochemical Results – Fasting Glucose – mg/dL *p<.05 compared to chlorthalidone

  29. Implications of FBS Differences with Antihypertensive Medications • Regimens with ACEIs/ARBs have 4-6 mg/dl lower FBS levels over 2-4 years vs other regimens: 0.5-1% difference in diabetes incidence/year. • Hgb A1c difference of 1%  FBS 35-40 mg/dl. • In ACCORD, a Hgb A1c difference of 1.5% (FBS 55-60 mg/dl) is projected to be needed to produce a significant difference in CVD events in 10,000 participants over 5 years. • This difference is 10X the difference produced by AHT drugs.

  30. ALLHAT 1 2 0.50 0.50 1 2 Favors Favors Amlodipine Chlorthal Diabetics & Nondiabetics (History)Amlodipine/Chlorthalidone Relative Risk and 95% Confidence Intervals Favors Favors Amlodipine Chlorthal JAMA 2002;288:2981-2997

  31. ALLHAT 0.50 1 2 Favors Favors Lisinopril Chlorthal 2 0.50 1 Diabetics & Nondiabetics (History)Lisinopril/Chlorthalidone Relative Risk and 95% Confidence Intervals Favors Favors Lisinopril Chlorthal JAMA 2002;288:2981-2997

  32. ALLHAT Conclusions - Overall Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy in most hypertensive patients, unless there is a compelling indication for another class.

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

  34. Questions?

  35. 16 14 12 10 8 6 16 16 4 14 14 12 12 10 10 2 8 8 6 6 0 4 4 2 2 0 0 0 6 6 6 12 12 12 18 18 18 24 24 24 30 30 30 36 36 36 42 42 42 48 48 48 54 54 54 60 60 60 66 66 66 0 0 LIFE: Cumulative Event Rates Primary Composite Endpoint Fatal/Nonfatal Stroke ARR 13.0%, P=.021 URR 14.6%, P=.009 ARR 24.9%, P=.001 URR 25.8%, P=.0006 16 14 Atenolol Atenolol 12 10 Patients With First Event (%) Losartan 8 Losartan 6 4 2 0 0 6 12 18 24 30 36 42 48 54 60 66 Fatal/nonfatal MI CV Mortality ARR -7.3%, P=NS URR -5.0%, P=NS ARR 11.4%, P=NS URR 13.3%, P=NS Atenolol Losartan Patients With First Event (%) Atenolol Losartan Study Month Study Month ARR=adjusted risk reduction; URR=unadjusted risk reduction.Dahlöf et al. Lancet. 2002;359:995-1003.

  36. VALUE Hazard Ratios for Pre-specified Analyses HazardRatio 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 0.5 1 2 Favours valsartan Favours amlodipine Julius S et al. Lancet. 2004;363:2022-2031.

  37. A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering in a factorial study design B.Dahlof (Co-chair), P.Sever (Co-chair), N. Poulter (Secretary) H. Wedel (Statistician), G. Beevers, M. Caulfield, R. Collins S. Kjeldsen, A. Kristinsson, J. Mehlsen, G. McInnes, M. Nieminen E. O’Brien, J. Östergren, on behalf of the ASCOT Investigators

  38. ASCOT-BPLA Design • Prospective, randomized, open-label, blinded endpoint (PROBE) • CCB  ACEI (“more contemporary regimen”) vs b-blocker  diuretic (“standard regimen”) • Primary endpoint: Nonfatal MI + fatal CHD • 19,257 participants • Mean follow-up: 5.4 years

  39. Patient inclusion criteria • Screening and baseline BP • 160/100 mm Hg untreated •  140/90 mm Hg following treatment with 1 or more drugs • Age 40-79 years • No previous MI or current clinical CHD • 3 or more CV risk factors

  40. Treatment algorithm to BP targets < 140/90 mm Hg or < 130/80 mm Hg in patients with diabetes amlodipine 5-10 mg atenolol 50-100 mg add add bendroflumethiazide-K 1.25-2.5 mg perindopril 4-8 mg add doxazosin GITS 4-8 mg add additional drugs, eg, moxonidine/spironolactone

  41. Systolic and diastolic blood pressure atenolol  thiazide amlodipine  perindopril 180 164.1 SBP 160 163.9 Mean difference 2.7 137.7 140 136.1 mm Hg 120 DBP 94.8 100 Mean difference 1.9 94.5 79.2 80 77.4 60 Last visit Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Time (years)

  42. Summary of all end points Unadjusted Hazard ratio (95% CI) 0.90 (0.79-1.02) 0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05) 1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.70 (0.63-.078) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92) PrimaryNon-fatal MI (incl silent) + fatal CHD SecondaryNon-fatal MI (exc. Silent) +fatal CHD Total coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure TertiarySilent MI Unstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 1.00 1.45 2.00 0.50 0.70 Atenolol  thiazide better Amlodipine  perindopril better The area of the blue square is proportional to the amount of statistical information

  43. ASCOT vs ALLHAT

  44. ALLHAT Results • Compared amlodipine vs chlorthalidone • Add-on drugs and achieved BP were similar • No difference in CHD outcome or stroke • 1/3 higher rates of HF with amlodipine

  45. Comments - Conclusions • β-blocker should not be used as initial therapy in uncomplicated hypertension • Inferior to ARB in LIFE • Inferior to CCB in ASCOT • Inferior to diuretic in MRC in Elderly • β-blocker inferior to thiazide diuretic in meta-analysis (Psaty) • Amlodipine is at least as good as ACEI (ALLHAT) and ARB (VALUE) and has shown comparable CVD reduction vs diuretic except for HF (ALLHAT, others)

  46. INVEST Design n=22,576 Calcium Antagonist Strategy Non-Calcium Antagonist Strategy Verapamil sustained release, 240 mg/d, plus trandolapril, 2 mg/d for patients with diabetes, renal impairment, or heart failure* Atenolol, 50 mg/d, Plus Trandolapril, 2 mg/d for Patients with Diabetes, Renal Impairment, or Heart Failure Step 1 Step 2Add Drug Atenolol, 50 mg/d, Plus Hydrochlorothiazide, 25 mg/d Verapamil sustained Release, 240 mg/d, Plus Trandolapril, 2 mg/d Step 3IncreaseDose Verapamil Sustained Release, 180 mg Twice Daily, Plus Trandolapril, 2 mg Twice Daily Atenolol, 50 mg Twice Daily, Plus Hydrochlorothiazide, 25 mg Twice Daily Verapamil Sustained Release, 180 mg Twice Daily, Plus Trandolapril, 2 mg Twice Daily, Plus Hydrochlorothiazide, 25 mg/d Atenolol, 50 mg Twice Daily, Plus Hydrochlorothiazide, 25 mg Twice Daily, Plus Trandolapril, 2 mg/d Step 4Add Drug MaximumTreatment Maximum Tolerated Dose, and/or Add Nonstudy Antihypertensive Medication Maximum Tolerated Dose, and/or Add Nonstudy Antihypertensive Medication Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org

  47. INVEST Primary and Secondary Outcomes by Treatment Group CAS = Calcium Antagonist Strategy; NCAS = Non-Calcium Antagonist Strategy Pepine CJ, et al. JAMA. 2003;290:2805-2816 www.hypertensiononline.org

  48. Selection of Initial Antihypertensive Drugs - 1 In JNC 7 we said: • “Excellent clinical trial outcome data prove that … ACE inhibitors, ARBs, b-blockers, CCBs and thiazide-type diuretics will all reduce the complications of HTN.” • “Thiazide-type diuretics should be used as initial therapy for most patients with HTN, either alone or in combination with one of the other classes (ACEIs, ARBs, BBs, CCBs) demonstrated to be beneficial in randomized controlled outcome trials.”

  49. Selection of Initial Antihypertensive Drugs - 2 • However, now I would say: older and newer trials suggest b-blockers should not be recommended as initial therapy in HTN without a compelling indication for the b-blocker. • I would modify the JNC 7 statements: • Clinical trial outcome data give preference to thiazide-type diuretics, CCBs, ACE inhibitors, and ARBs in the management of HTN. • Thiazide-type diuretics should be used as initial therapy for most patients with HTN, either alone or in combination with ACEIs, ARBs, and/or CCBs.

  50. Effect of DM on Mortality – 14.3 Years Follow-Up Baseline diabetes / No diabetes Adjusted RR (95% CI) All-cause mortality Active 1.376 (1.161 – 1.631) Placebo 1.633 (1.397 – 1.907) CVD mortality Active 1.458 (1.138 – 1.868) Placebo 1.838 (1.484 – 2.276) Follow-up diabetes / No diabetes All-cause mortality Active 1.151 (0.925 – 1.433) Placebo 1.348 (1.051 – 1.727) CVD mortality Active 1.043 (0.745 – 1.459) Placebo 1.562 (1.117 – 2.184) 0.50 1 2 Survival better Survival worse 3

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