The Relationship of Systolic and Diastolic Blood Pressure to Cardiovascular Disease Risk: Observational DataPrevalence of Hypertension in the USPrevalence of Hypertension in the USPercent hypertensive18-29Based on NHANES III (phase 1 and 2)Hypertension defined as blood pressure 140/90 mmHg or treatment30-3940-4950-5960-6970-7980+Age3 %9 %18 %38 %51 %66 %72 %JNC-VI. Arch Intern Med. 2019;157:2413-2446.Risk of hypertension (%)Residual lifetime risk of developing hypertension among people with blood pressure 140/90 mmHgYearsLifetime Risk of Developing Lifetime Risk of Developing Hypertension Beginning at Age 65Hypertension Beginning at Age 65MenWomenVasan RS, et al. JAMA. 2019; 287:1003-1010.Copyright 2019, American Medical Association.Mortality According to Blood Pressure Mortality According to Blood Pressure in Men Age 50 to 69in Men Age 50 to 69Society of Actuaries. Blood Pressure Study, 1939.Ratio (%) of actual to expected mortalitySystolic blood pressure (mmHg)Diastolic blood pressure (mmHg)Age-adjusted annualincidence of CHD per 1000Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart disease (CHD) at baselineSystolic blood pressure (mmHg)Blood Pressure and Risk for Blood Pressure and Risk for Coronary Heart Disease in MenCoronary Heart Disease in MenDiastolic blood pressure (mmHg)Age 65-94Age 65-94Age 35-64Age 35-64Age 65-94Age 65-94Age 35-64Age 35-64Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.Relative risk of CHD mortality He J, et at. Am Heart J. 2019;:211-219.Copyright 2019, Mosby Inc.11215198(lowest 10%)(highest 10%)SBP (mmHg)DBP (mmHg)Systolic blood pressure (SBP)Diastolic blood pressure (DBP)CHD=coronary heart diseaseRelative risk of stroke death 11215198(lowest 10%)(highest 10%)SBP (mmHg)DBP (mmHg)Systolic blood pressure (SBP)Diastolic blood pressure (DBP)He J, et at. Am Heart J. 2019;:211-219.Copyright 2019, Mosby Inc.Age-adjusted annual CVD event rate per 1000Wilking SV et al. JAMA. 1988;260:3451-3455.MenWomenIsolated Systolic Hypertension Isolated Systolic Hypertension and CVD Risk in Framinghamand CVD Risk in FraminghamISH BP 160/95 mmHgBP 140/95 mmHg8243332.4182.5CVD=cardiovascular disease ISH=isolated systolic hypertensionP0.001 for difference between both men and women with ISH and blood pressure (BP) 140/95 mmHgThe Relationship of Hypertension Treatment to CVD Risk Reduction:IntroductionIncidence of cardiovascular disease120Hypertension Treatment Effect Mirrors Observational Data140160180200220Observational DataObservational DataTreatment EffectSystolic blood pressure (mmHg)Landmark Clinical TrialsLandmark Clinical TrialsHypertension Treatment and Hypertension Treatment and Cardiovascular Disease OutcomesCardiovascular Disease Outcomes1967 VA Cooperative Study on DBP 115-1291970 VA Cooperative Study on DBP 90-1141979 HDFP1980 Australian Trial, Oslo Trial1985 MRC I, EWPHE1991 SHEP, STOP-Hypertension 1992 MRC II in the elderly2019 Syst-Eur 2019 LIFE2019 ALLHATVeterans Administration, 1967Veterans Administration, 1970Hypertension Stroke Study, 1974USPHS Study, 1977EWPHE Study, 1985Coope and Warrender, 1986SHEP Study, 1991STOP-Hypertension Study, 1991MRC Study, 1992Syst-Eur Study, 2019TotalRelative Risk for Coronary Heart DiseaseRelative Risk for Coronary Heart DiseaseOdds ratios and95% confidence intervals00.511.520.79(0.69 to 0.90)He J, et al. Am Heart J. 2019; :211-219.Copyright 2019, Mosby, Inc.Active treatment better than placeboActive treatment worse than placeboVeterans Administration, 1967Veterans Administration, 1970Hypertension Stroke Study, 1974USPHS Study, 1977EWPHE Study, 1985Coope and Warrender, 1986SHEP Study, 1991STOP-Hypertension Study, 1991MRC Study, 1992Syst-Eur Study, 2019TotalRelative Risk for Stroke 00.511.520.63(0.55 to 0.72)Odds ratios and95% confidence intervalsActive treatment better than placeboActive treatment worse than placeboHe J, et al. Am Heart J. 2019; :211-219.Copyright 2019, Mosby, Inc.The Veterans Administration Cooperative Study on Antihypertensive AgentsThe VA Cooperative Study, 1967Cohort143 menMean age51 yearsEligibilityDiastolic BP 115-129 mmHgDesignDouble blind; placebo controlTherapyHCTZ, reserpine, hydralazineDuration1.5 yearsBP change-43/30 mmHgVA Cooperative Study Group. JAMA. 1967;202:1028-1034.HCTZ=hydrochlorothiazide -1212The VA Cooperative Study, 1967: The VA Cooperative Study, 1967: Change in Systolic and Diastolic Blood PressureChange in Systolic and Diastolic Blood PressureChange in Systolic BP (mmHg)Percent of patientsPercent of patientsChange in Diastolic BP (mmHg)-76 -60 -44 -28028Decrease (-)(+) IncreaseActive drugsPlaceboActive drugsPlaceboVA Cooperative Study Group. JAMA. 1967;202:1028-1034.Copyright 1967, American Medical Association.-1212-76 -60-44 -28028Decrease (-)(+) IncreaseThe VA Cooperative Study, 1967:The VA Cooperative Study, 1967:Assessable Morbid/Fatal EventsAssessable Morbid/Fatal EventsPlacebon=70Active Rx*n=73 Accelerated hypertension120Stroke41Coronary event20CHF20Renal damage20Deaths40VA Cooperative Study Group. JAMA. 1967;202:1028-1034.*P0.001 active drug therapy vs placebo The VA Cooperative Study, 1967:ConclusionsThe actively treated group experienced a reduction in multiple hypertension-related endpoints21 morbid/fatal events on placebo1 morbid/fatal event on active therapyVA Cooperative Study Group. JAMA. 1967;202:1028-1034.The VA Cooperative Study, 1970Cohort380 menMean age50 yearsEligibilityDiastolic BP 90-114 mmHgDesignDouble blind; placebo controlTherapyHCTZ, reserpine, hydralazineDuration5.5 years (mean=3.8 yrs)BP changeDiastolic BP -19 mmHgVA Cooperative Study Group. JAMA. 1970;213:1143-1152.PlaceboPlacebon=194n=194Active Rx*Active Rx*n=186 n=186 Accelerated hypertension40Stroke205Total coronary event1311Fatal coronary event116Congestive heart failure110Renal damage30Deaths198The VA Cooperative Study, 1970:Assessable Morbid/Fatal EventsVA Cooperative Study Group. JAMA. 1970;213:1143-1152.*P 60 yrs old; mean 72 yrs oldEligibilitySystolic BP 150 239 mmHg; diastolic BP 90 119 mmHgDesignDouble blind; placebo controlTherapyHCTZ, triamtereneDuration4.7 yearsBP change-21/10 mmHg at 5 yearsAmery A, et al. Lancet. 1985;1:1349-4. Survival free of event (%)Year of follow-upEWPHE Cardiovascular Mortality On-Treatment AnalysisActive (n=416)Placebo (n=424)P=0.02301362457Amery A, et al. Lancet. 1985;1:1349-4.Reprinted with permission from Elsevier Science. EWPHE=European Working Party on High Blood Pressure in the Elderly EWPHEConclusionsActive treatment reduced cardiovascular (CV) mortality, largely due to a reduction in cardiac mortalityOlder patients (60 yrs old) with combined systolic and diastolic hypertension who received active therapy experienced 29 fewer CV events and 14 fewer CV deaths per 1,000 patient-years of treatmentAmery A, et al. Lancet. 1985;1:1349-4. EWPHE=European Working Party on High Blood Pressure in the Elderly The Hypertension Detection and Follow-up Program, 1979The Hypertension Detection and Follow-up Program, 1979Cohort10,940; 54% men; 44% blackAge30 69 yrs old; mean 50.8 yrs oldEligibilityDiastolic BP 90 mmHgDesignStepped Care vs Referred CareTherapyChlorthalidone (reserpine, methyldopa)Duration5 yearsBP change5 mmHg (Stepped Care vs Referred Care)HDFP Cooperative Group. JAMA. 1979;242:2562-2571. Cumulative mortality (%)0136Year of follow-upHDFP Mortality RatesEntire Cohort245Referred CareStepped CareHDFP=Hypertension Detection and Follow-up Program *P0.01 HDFP Cooperative Group. JAMA. 1979;242:2562-2571. (n=5,456) (n=5,485) *0136245Cumulative mortality (%)HDFP Mortality RatesDiastolic BP 90 104 mmHgReferred CareStepped CareHDFP=Hypertension Detection and Follow-up Program Year of follow-up*P0.01 HDFP Cooperative Group. JAMA. 1979;242:2562-2571. (n=3,822) (n=3,903) *BP=blood pressureHDFPConclusionsOverall, stepped care (SC) compared to referred care (RC) reduced total mortality by 17% (6.4 vs. 7.7%; P0.01)In patients with baseline diastolic blood pressure 90 104 mmHg (n=7,725), mortality was reduced by 20% with SC vs. RC (5.9% vs. 7.4%; P0.01)Aggressive treatment of SC patients with the lowest baseline diastolic blood pressures (90 94 and 95 99 mmHg) reduced mortalityHDFP=Hypertension Detection and Follow-up Program HDFP Cooperative Group. JAMA. 1979;242:2562-2571. The Systolic Hypertension in the Elderly Program, 1991The Systolic Hypertension in the Elderly Program, 1991SHEP Research Group. JAMA. 1991;265:3255-3264.Cohort4,736; 43% menAge 60 yrs old; mean 71.6 yrs oldEligibilitySystolic BP 160 219 mmHg and Diastolic BP 90 mmHgDesignDouble blind; placebo controlTherapyChlorthalidone (atenolol as step 2)Duration4.5 yearsBP changeSystolic BP 12 mmHgBP=blood pressureChange in BP (mmHg)YearsSHEPChange in Blood PressurePlacebo (n=2,371)Active Rx (n=2,365)Years012345012345Systolic BPSystolic BPDiastolic BPDiastolic BPSHEP Research Group. JAMA. 1991;265:3255-3264.Copyright 1991, American Medical Association.BP=blood pressureSHEP=Systolic Hypertension in the Elderly Program Placebo (n=2,371)Active Rx (n=2,365)Blood pressure (mmHg)0123660Months of follow-upSHEPSHEPAverage Blood Pressure During Follow-upAverage Blood Pressure During Follow-up24480SHEP=Systolic Hypertension in the Elderly Program SHEP Research Group. JAMA. 1991;265:3255-3264.Copyright 1991, American Medical Association.Cumulative stroke rate per 100 persons0123660Months of follow-upSHEPSHEPCumulative Stroke RateCumulative Stroke Rate244872P=0.0003Placebo(n=2,371)Active Rx (n=2,365)SHEP=Systolic Hypertension in the Elderly Program SHEP Research Group. JAMA. 1991;265:3255-3264.Copyright 1991, American Medical Association.Relative risk (95% CI)StrokeCHDActive Therapy vs. PlaceboCHFDeath0.630.630.460.460.680.680.870.87CVD0.750.75SHEPSHEPCardiovascular Disease EndpointsCardiovascular Disease EndpointsSHEP Research Group. JAMA. 1991;265:3255-3264.SHEP=Systolic Hypertension in the Elderly Program CHD=coronary heart disease; CHF=congestive heart failure; CVD=cardiovascular disease SHEPConclusionsSHEP was the first clinical trial to demonstrate that reduction of blood pressure in patients with isolated systolic hypertension reduced cardiovascular (CV) mortalityThe relative risk of stroke was reduced by 36% with therapy compared to placebo (P=0.0003)The 5-year absolute benefits were a reduction in 30 strokes and 55 major CV disease events per 1,000 personsSHEP Research Group. JAMA. 1991;265:3255-3264.SHEP=Systolic Hypertension in the Elderly Program The Systolic Hypertension in Europe (Syst-Eur) Trial, 2019The Systolic Hypertension in Europe Trial, 2019Cohort4,695; 67% womenAge 60 yrs oldEligibilitySystolic BP 160219 mmHg and diastolic BP 95 mmHgDesignDouble blind; placebo controlTherapyNitrendipine (enalapril, HCTZ as Step 2)DurationMedian 2 yrs (1-97 months)BP difference-10/5 mmHgStaessen JA, et al. Lancet. 2019;350:757-764.Systolic BP (mmHg)Syst-Eur Mean Sitting Systolic Blood Pressure0Placebo (n=2,297)Active treatment (n=2,398) 1234Years since randomizationStaessen JA, et al. Lancet. 2019;350:757-764.Reprinted with permission from Elsevier Science.Syst-Eur=Systolic Hypertension in Europe Trial P0.001Syst-Eur Mean Sitting Diastolic Blood Pressure01234Diastolic BP (mmHg)Placebo (n=2,297)Active treatment (n=2,398) P0.001Years since randomizationStaessen JA, et al. Lancet. 2019;350:757-764.Reprinted with permission from Elsevier Science.Syst-Eur=Systolic Hypertension in Europe Trial Events per 100 patientsSyst-Eur Primary EndpointFatal and Nonfatal StrokePlacebo (n=2,297)Active treatment (n=2,398) 01342P=0.003Years since randomizationStaessen JA, et al. Lancet. 2019;350:757-764.Reprinted with permission from Elsevier Science.Syst-Eur=Systolic Hypertension in Europe Trial Percentage relative risk reduction (95% CI)StrokeMIActive therapy vs. placeboCHFDeath42%42%P=0.00P=0.003 329%29%31%31%P0.0P0.0010114%14%All CVD30%30%Syst-EurCardiovascular Disease EndpointsStaessen JA, et al. Lancet. 2019;350:757-764.MI=myocardial infarction; CHF=congestive heart failure; CVD=cardiovascular disease Syst-Eur=Systolic Hypertension in Europe Trial Syst-Eur ConclusionsOlder men and women with isolated systolic hypertension who received active treatment with a dihydropyridine calcium channel blocker experienced fewer strokes and cardiovascular disease (CVD) events than those receiving placebo.Treatment of 1,000 patients for 5 years with this type of regimen could prevent 29 strokes or 53 major CVD endpoints.Staessen JA, et al. Lancet. 2019;350:757-764.Syst-Eur=Systolic Hypertension in Europe Trial The Australian National Blood Pressure (ANBP) Study, 1980The Australian National Blood Pressure Study, 1980The Australian Study Committee. Lancet. 1980;1:1261-1267.Cohort3,427; 80% menAge3069 yrs oldEligibilityDiastolic BP 95109 mmHgDesignSingle blind; placebo controlTherapyChlorothiazide (methyldopa, beta blocker)Duration4 yrsBP difference-6 mmHgThe Australian Study Mean Diastolic Blood PressureDiastolic blood pressure (mmHg)The Australian Study Committee. Lancet. 1980;1:1261-1267.The Australian Study Incidence of Trial Endpoints (TEP)*Intention-to-treatPlacebo (n=1,706)Active (n=1,721)No.RateNo.RateTotal Fatal TEP 35 5.125 3.6 Cardiovascular 18 2.68 1.1 Non-cardiovascular 17 2.517 2.4Non-fatal TEP13319.411316.2All TEP16824.5138 19.7*Rates per 1,000 person-years exposure to risk.P0.05 P0.025The Australian Study Committee. Lancet. 1980;1:1261-1267.The Australian Study Intention-to-Treat Trial EndpointsNo. of eventsPlacebon=1,706Activen=1,721Ischemic heart disease Fatal115 Nonfatal myocardial infarction2228 Nonfatal other7665Cerebrovascular events Fatal63 Nonfatal Hemorrhage or thrombosis1610 Transient cerebral ischemic attacks94Other fatal1817Other nonfatal106The Australian Study Committee. Lancet. 1980;1:1261-1267.The Australian Study On-Treatment Trial Endpoints (TEP)Number of trial endpointsDays in trial200016001200600400All TEPP0.01All Fatal TEPP0.05Active (n=1,721)Placebo (n=1,706)The Australian Study Committee. Lancet. 1980;1:1261-1267.Reprinted with permission from Elsevier Science.The Australian Study ConclusionsThe actively treated compared to placebo group experienced 30 fewer trial endpoints endpoints (P0.05)There was a significant reduction in mortality in the actively treated group, mostly due to a reduction in death from cardiovascular disease (P0.025)The Australian Study Committee. Lancet. 1980;1:1261-1267.