Daily Dilemmas in Hypertension Management

Objectives Review the impact of hypertension on society Review the impact of hypertension on society Review several current questions in hypertension management Review several current questions in hypertension management

Joint National Committee (JNC7) BP Classification SBP DBP Normal <120 and <80 Pre Hypertension or Stage I Hypertension 140 – 159 or Stage II Hypertension > 160 or > 100

Ong, et al. Hypertension, 2007

Healthy People 2010 Reduce prevalence of HTN to 16% (at 28% in 2000) Reduce prevalence of HTN to 16% (at 28% in 2000) Target 50% overall hypertension control rate Target 50% overall hypertension control rate Target 95% intervention rate (including life style modification) Target 95% intervention rate (including life style modification)

Ong, et al. Hypertension, 2007

Treatment of Hypertension Not at Goal Blood Pressure Initial Drug Choices Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Lifestyle Modifications Stage 2 Hypertension 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Not at Goal Optimize dosages or add additional drugs until goal blood pressure is achieved. Adapted from JNC7

Treatment Options Diuretics Adrenergic Blockers Vasodilators ThiazidesChlorthalidoneIndapamideMetolazoneThiazidesLoopsBumetanideFurosimideToremide Aldosterone blockers SpironaldactoneEplerenone Potassium sparers AmilorideTriamterene Peripheral Inhibitors GuanadrelGuanethidineReserpine Central alpha- agonists ClonidineGuanzbenzGuanfacineMethyldopaAlpha-blockersDozazosinPrazosinTerazosinBeta-blockersAcebutolAtenololBetaxololBisoprololCarteololMetoprololNadololPenutololPindololPropranololTimololCombinedCarvediolLabetololDirectHydralazineMinoxidil Calcium channel blocker Dihydropyridines Amlodipine Amlodipine Felodipine Felodipine Isradipine Isradipine Nicardipine Nicardipine Nifedipine Nifedipine Nisoldipine NisoldipineDiltiazemVerapamil Direct renin antagonist AliskirenACE-IBenazeprilCaptoprilEnalaprilFosinoprilLisinoprilMoexiprilQuinaprilPerindoprilRamiprilTrandolaprilARBCandesartanEprosartanIrbesartanLosartanTelmisartanValsartan

The Lancet, Volume 362, Issue 9395, 2003 Comparisons of Therapy

Benefits of Lowering Blood Pressure Average Percent Reduction Stroke incidence 35–40% Myocardial infarction20-25% Heart failure50%

Question #1 I have a 86 year-old Caucasian female patient with osteoporosis and a history of breast cancer. Here clinic blood pressure is always 190/80. I have a 86 year-old Caucasian female patient with osteoporosis and a history of breast cancer. Here clinic blood pressure is always 190/80. What should be her target systolic blood pressure? What should be her target systolic blood pressure?

Scope of the Problem

DBP (mm Hg) SBP (mm Hg) DBP (mm Hg) SBP (mm Hg) DBP (mm Hg) SBP (mm Hg) DBP (mm Hg) SBP (mm Hg) Men, Age (y)Women, Age (y) Non-Hispanic Black Non-Hispanic White Mexican American Pulse pressure Mean Systolic and Diastolic BP by Age and Race/Ethnicity for Men and Women (US Population ³Age 18 Years, NHANES III) Burt VI, et al. Hypertension. 1995;25:

Benefits of Lowering Blood Pressure Average Percent Reduction Stroke incidence 35–40% Myocardial infarction20-25% Heart failure50%

Cumulative stroke rate per 100 persons Months of follow-up SHEP Cumulative Stroke Rate P= Placebo (n=2,371) Active Rx (n=2,365) SHEP=Systolic Hypertension in the Elderly Program SHEP Research Group. JAMA. 1991;265: Copyright ©1991, American Medical Association. Hypertensiononline.org 36% reduction in stroke rate

Relative risk (95% CI) StrokeCHD Active Therapy vs. Placebo CHFDeath CVD 0.75 SHEP Cardiovascular Disease Endpoints SHEP Research Group. JAMA. 1991;265: SHEP=Systolic Hypertension in the Elderly Program CHD=coronary heart disease; CHF=congestive heart failure; CVD=cardiovascular disease Hypertensiononline.org

Survival free of event (%) Year of follow-up EWPHE Cardiovascular Mortality On-Treatment Analysis Active (n=416) Placebo (n=424) P= Amery A, et al. Lancet. 1985;1: Reprinted with permission from Elsevier Science. EWPHE=European Working Party on High Blood Pressure in the Elderly Hypertensiononline.org

Blood Pressure & The Very Elderly Epidemiologic population studies suggest better survival with higher levels of blood pressure Epidemiologic population studies suggest better survival with higher levels of blood pressure Worse survival reported in hypertensives with SBP levels below 140 mmHg (Oates et al. 2007) Worse survival reported in hypertensives with SBP levels below 140 mmHg (Oates et al. 2007) Meta-analysis (n=1670) (Gueyffier et al. 1997) Meta-analysis (n=1670) (Gueyffier et al. 1997) 36% reduction in the risk of stroke (BENEFIT) 36% reduction in the risk of stroke (BENEFIT) 14% (p=0.05) increase in total mortality (RISK) 14% (p=0.05) increase in total mortality (RISK)

The Trial: International, multi-centre, randomised double-blind placebo controlled Inclusion Criteria: Exclusion Criteria: Aged 80 or more,Standing SBP < 140mmHg Systolic BP; mmHg Stroke in last 6 months + diastolic BP; <110 mmHg, Dementia Informed consentNeed daily nursing care CHF or Cr more than 1.7 Primary Endpoint: All strokes (fatal and non-fatal ) Target blood pressure 150/80 mmHg

All stroke (30% reduction) Placebo IndapamideSR ±perindopril

Heart Failure (64% reduction)

Total Mortality (21% reduction)

Conclusions Antihypertensive treatment based on indapamide ± perindopril reduced stroke mortality and total mortality in a very elderly cohort. Antihypertensive treatment based on indapamide ± perindopril reduced stroke mortality and total mortality in a very elderly cohort. NNT (2 years) = 94 for stroke and 40 for mortality NNT (2 years) = 94 for stroke and 40 for mortality Large and significant benefit in reduction of heart failure events and for combined endpoint of cardiovascular events Large and significant benefit in reduction of heart failure events and for combined endpoint of cardiovascular events Goal blood pressure was 150/80 Goal blood pressure was 150/80

INVEST Trial Secondary analysis The risk for the primary endpoint (death, myocardial infarction, or stroke) progressively increased with low diastolic blood pressure. The risk for the primary endpoint (death, myocardial infarction, or stroke) progressively increased with low diastolic blood pressure. AIM 144:884 (2006)

Conclusions Evidence supports moderate blood pressure reduction in the very elderly to goal of 150/80 Evidence supports moderate blood pressure reduction in the very elderly to goal of 150/80 Excessive reduction of diastolic pressure may have adverse consequences Excessive reduction of diastolic pressure may have adverse consequences

My Patient Target blood pressure of 150/80 Target blood pressure of 150/80 Achieve goal with low dose thiazide diurectic Achieve goal with low dose thiazide diurectic Consider ACE-I or CCB for combination therapy Consider ACE-I or CCB for combination therapy Monitor home blood pressures Monitor home blood pressures Consider titrating to standing blood pressure Consider titrating to standing blood pressure

Question #2 Is combination therapy with an angiotensin-converting enzyme inhibitor (ACE) and an angiotensin receptor blocker (ARB) appropriate for my patient with essential hypertension requiring an additional agent to reach goal? Is combination therapy with an angiotensin-converting enzyme inhibitor (ACE) and an angiotensin receptor blocker (ARB) appropriate for my patient with essential hypertension requiring an additional agent to reach goal?

Renin-Angiotensin Pathway

Practice Trends Since 2000, several trials compared dual ACE-ARB therapy in nephropathy and coronary disease Since 2000, several trials compared dual ACE-ARB therapy in nephropathy and coronary disease COOPERATE, CHARM, VALLIANT, ONTAGERT COOPERATE, CHARM, VALLIANT, ONTAGERT General thought: More blockade must be better General thought: More blockade must be better

COOPERATE Evaluated combination of losartan and trandolapril in non-diabetic proteinuric renal disease Evaluated combination of losartan and trandolapril in non-diabetic proteinuric renal disease Significant benefit from combination therapy in slowing progression of disease Significant benefit from combination therapy in slowing progression of disease Publication retracted by the Lancet in October 2009 Publication retracted by the Lancet in October 2009 Lancet 2003 Jan 11;361(9352): Lancet 2009 Oct 9;374(9697):1226

ACE and ARB medications equally reduce proteinuria ACE and ARB medications equally reduce proteinuria Combination therapy has greater effect Combination therapy has greater effect Unable to assess outcomes Unable to assess outcomes Ann Intern Med Jan 1;148(1):30-48

Effects of telmisartan, ramipril, or both on death from cardiovascular causes, MI, stroke, or hospitalization for heart failure Effects of telmisartan, ramipril, or both on death from cardiovascular causes, MI, stroke, or hospitalization for heart failure No significant difference in primary outcomes between any arms No significant difference in primary outcomes between any arms ONTARGET NEJM 2008; 358:

ONTARGET Dual Therapy Average BP reduction of 2-3 mmHg in combination arm Average BP reduction of 2-3 mmHg in combination arm Expected 4-5% reduction in primary outcome not found Expected 4-5% reduction in primary outcome not found Significant increases in: Significant increases in: Hypotension Hypotension Hyperkalemia Hyperkalemia Renal dysfunction Renal dysfunction Syncope Syncope NEJM 2008; 358:

ONTARGET Conclusions Patients who have vascular disease or high risk diabetes, telmisartan is not inferior to ramipril Patients who have vascular disease or high risk diabetes, telmisartan is not inferior to ramipril No additional benefit from combination therapy No additional benefit from combination therapy Significantly more risk Significantly more risk BP reduction not beneficial BP reduction not beneficial NEJM 2008; 358:

My Patient ACE or ARB is appropriate ACE or ARB is appropriate Combination therapy not routinely indicated for blood pressure reduction Combination therapy not routinely indicated for blood pressure reduction Specific populations may have benefit from combination therapy Specific populations may have benefit from combination therapy Consider other options for proteinuria reduction if indicated Consider other options for proteinuria reduction if indicated

Question #3 I have a 50 year-old male patient with elevated systolic blood pressures over 160 mmHg at every clinic visit. His home blood pressure is always less than 130 mmHg. I have a 50 year-old male patient with elevated systolic blood pressures over 160 mmHg at every clinic visit. His home blood pressure is always less than 130 mmHg. What is his cardiovascular risk from his elevated clinic readings? What is his cardiovascular risk from his elevated clinic readings?

Hypertension 1987;9:209

White Coat Hypertension Definition: Definition: Daytime blood pressure average less than 130/80 mmHg Daytime blood pressure average less than 130/80 mmHg Clinic readings greater than 140/90 mmHg Clinic readings greater than 140/90 mmHg White Coat Effect White Coat Effect Elevated pressure in the clinic superimposed on essential hypertension Elevated pressure in the clinic superimposed on essential hypertension

Scope of the Problem Prevalence range 10 – 30% of patients with clinical hypertension Prevalence range 10 – 30% of patients with clinical hypertension Diagnosis of hypertension usually made on clinic blood pressure recordings Diagnosis of hypertension usually made on clinic blood pressure recordings 10% - 74% will progress to hypertension over 5 years 10% - 74% will progress to hypertension over 5 years Historically considered a benign condition Historically considered a benign condition

Outcomes in White Coat Hypertension (WCH) P<0.001 NS Khatter et al, Circulation. 1998;98:1892

Hypertension. 2005;45: Analysis of data from 4 cohort studies in 3 countries Analysis of data from 4 cohort studies in 3 countries Followed for a median 5.3 years Followed for a median 5.3 years Evaluated incidence of stroke Evaluated incidence of stroke

Results Significant increased risk of stroke from: Significant increased risk of stroke from: Elevated office and sleep systolic pressure Elevated office and sleep systolic pressure Tobacco use Tobacco use Older age Older age Diabetes Diabetes No clear significant increased risk from white coat hypertension No clear significant increased risk from white coat hypertension

Six-Year Risk-Factor Adjusted Probability of Stroke Hypertension. 2005;45: Non-SmokersSmokers

Cumulative Hazard for Stroke Hypertension. 2005;45:

Conclusions Patients with white coat hypertension are at risk for progression to hypertension, likely greater than a normotensive cohort Patients with white coat hypertension are at risk for progression to hypertension, likely greater than a normotensive cohort While the cardiovascular risk from WCH is less than with hypertension, it may still carry some risk While the cardiovascular risk from WCH is less than with hypertension, it may still carry some risk

My Patient Cardiac risk stratification from other risk factors Cardiac risk stratification from other risk factors Lifestyle modification Lifestyle modification Low sodium diet Low sodium diet Regular exercise Regular exercise Occasional home blood pressure monitoring Occasional home blood pressure monitoring Consider 24 hour ambulatory blood pressure monitor Consider 24 hour ambulatory blood pressure monitor

Conclusions To meet blood pressure goals we must: To meet blood pressure goals we must: Make the diagnosis more frequently Make the diagnosis more frequently Educate our patients Educate our patients Treat more aggressively, with simple medication regimens Treat more aggressively, with simple medication regimens Reassess to reach goals Reassess to reach goals

Thank you

Resources Amery A, et al. Lancet. 1985;1: Ann Med 2006; 144:884 Burt VI, et al. Hypertension. 1995;25: Hypertension. 1987;9:209 Hypertension. 2005;45: Khatter et al; Circulation. 1998;98:1892 Lancet 2003;361(9352): Lancet 2003; 362 (9395): Ong, et al. Hypertension SHEP Research Group. JAMA. 1991;265: