Blood Pressure Goals for Diabetic Patients Over 60 Years of Age: Is It Time They Earned Some Slack?

Ashley Marshall, PharmD PGY-1 Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center The University of Texas Health Science Center at San Antonio

January 30, 2015

Objectives:

1. Describe the pathophysiology and risk factors associated with hypertension in diabeticpatients

2. Compare the benefits and precautions in treating elevated blood pressures in the elderly3. Review the evidence supporting current guideline blood pressure goal recommendations in

the elderly4. Formulate a recommendation regarding blood pressure goals in elderly diabetics based on

evaluation of published literature

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Age (years)

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BACKGROUND

I. Hypertension (HTN)1 A. Epidemiology

i. Affects approximately 77.9 million adults in the United Statesii. One in three adults will develop HTN in their lifetime

iii. Estimated health care cost in 2009 was $51.0 billioniv. Prevalence increases with age

a. 18-39 years: 6.8%b. 40-59 years: 30.4%c. 60 years: 66.7%

v. Differences in sexa. <45 years: men>womenb. 45 to 64 years: men=womenc. 65 years: women>men

Figure 1. Percentage of Patients with Hypertension1

B. What is HTN?2-3 i. Definition

a. Systolic blood pressure (SBP) ≥140 mmHgb. Diastolic blood pressure (DBP) ≥90 mmHg

ii. Blood Pressure (BP)=Cardiac Output (CO) x Total Peripheral Resistance (TPR)a. CO=Heart Rate x Stroke Volumeb. ↑CO↑SBPc. ↑TPR↑DBP

iii. Causesa. Primary Hypertensionb. Secondary Hypertension

1. Chronic kidney disease2. Cushing syndrome3. Parathyroid/thyroid disease4. Pheochromocytoma5. Primary aldosteronism6. Medications

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iv. Diagnosis a. Mean of two or more seated readings b. Consisting of two or more separate appointments

v. Isolated Systolic Hypertension a. Defined as SBP >140 mmHg and DBP <90 mmHg b. Present in >25% of those ≥80 years of age c. Caused by decrease in elasticity of arterial wall

Table 1. Classification4

Category SBP, mmHg DBP, mmHg

Normal < 120 < 80

Pre-hypertension 120-139 80-89

Stage I Hypertension 140-159 90-99

Stage II Hypertension 160 100

C. Pathophysiology2

i. Renin-angiotensin-aldosterone system (RAAS) a. Increase release of renin from juxtaglomerular cells in kidney b. Renin catalyzes angiotensinogen to angiotensin I c. Angiotensin-converting enzyme (ACE) converts angiotensin I to

angiotensin II (ATII) d. ATII is a potent vasoconstrictor ↑TPR

ii. Aldosterone a. ATII promotes aldosterone synthesis and release b. Increase sodium and water retention ↑blood volume c. Promotes tissue remodeling and vascular dysfunction

iii. Sympathetic Nervous System (SNS) activation a. ↑TPR b. ↑HR c. ↑Heart contractility ↑CO

D. Risk factors for developing HTN1

i. Age

ii. Ethnicity a. Highest prevalence in blacks, particularly black females b. Blacks develop higher blood pressures earlier in life

iii. Family history of hypertension and genetic factors iv. Lower education and socioeconomic status v. Overweight/obese

vi. Lower physical activity vii. Tobacco use

viii. Psychosocial stressors ix. Sleep apnea x. Dietary factors

a. Dietary fats

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b. Higher sodium intake c. Lower potassium intake d. Excessive alcohol intake

E. Complications from untreated HTN1 i. Myocardial infarction (MI)

ii. Stroke iii. Chronic kidney disease (CKD) iv. Heart failure (HF) v. Retinopathy

vi. Death a. Primary or contributing cause of death in over 348,000 patients b. On average, total life expectancy ↓ by 5 years

vii. Benefits seen with even small reduction of 5mmHg in SBP5 a. Reduction in total cardiovascular (CV) risk: 20% b. Reduction in stroke: 30% c. Reduction in MI: 25%

II. Diabetes Mellitus (DM)1,6

A. Definition i. Hemoglobin A1c 6.5%

ii. Fasting plasma glucose 126 mg/dL iii. 2-hour plasma glucose 200 mg/dL during an oral glucose tolerance test iv. A random plasma glucose 200 mg/dL with symptoms of hyperglycemia

a. Polyuria b. Polydipsia c. Polyphagia

v. If hyperglycemia not absolute, testing should be repeated to confirm results B. Epidemiology

i. Approximately 29 million with DM a. Nine percent of total population

b. Twenty-seven percent of adults 65 years of age c. Men 13.6% vs women 11.2%

ii. Over eight million with undiagnosed DM iii. Over 87 million with prediabetes

C. Pathophysiology i. Insulin resistance

a. Inability to metabolize glucose properly b. Potentiated by obesity

ii. Impaired insulin secretion a. Insufficient insulin production and release from beta-cells in pancreas b. Most patients with 50% loss of beta-cell function at diagnosis

D. Risk factors of DM i. On average, total life expectancy ↓ by six years

ii. Macrovascular a. Coronary heart disease (CHD)

1. Over 68% of deaths in diabetics >65 years of age 2. Two to four times higher than adults without diabetes

b. Cerebrovascular events c. Peripheral artery disease

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iii. Microvasculara. Nephropathyb. Retinopathyc. Neuropathy

BENEFIT OF BP TREATMENT

I. DM and HTN6-7 A. Prevalence

i. HTN present in 75-85% of patients with DMii. Higher risk due to overlapping complications

B. Risk Reduction i. After BP treatment, diabetics had same macrovascular risks as non-diabetics

ii. Relative risk reductiona. Diabetic: 59%b. Non-diabetic: 33%

iii. Absolute risk reduction per 1000 patients treated for five yearsa. Diabetic: 221 CV event preventedb. Non-diabetic: 51 CV events prevented

Figure 2. Risk Reduction in Syst-China Trial7

II. Benefit in Elderly: The Blood Pressure Lowering Treatment Trialists’ Collaboration8

A. Purpose i. CV morbidity and mortality with lowering blood pressure

ii. Younger (<65 years of age) vs older patients (≥65 years of age)B. Methods

i. Meta-analysis of 31 trialsii. Total of 90,606 patients

iii. Primary outcome: total major CV events including stroke, CHD and HFC. Results

i. Similar benefit in younger and older patients in percentage risk reduction per 5mmHg decrease in blood pressure (p=0.38)

a. Age <65 years: 11.9% (5.3% to 18.0%)

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b. Age ≥65 years: 9.1% (3.6% to 14.3%)ii. No difference in effect of different medication classes between age groups

D. Conclusion i. Benefit of treating hypertension is present regardless of age

ii. Similar percentage risk reduction but absolute risk reduction increases as ageincrease

III. Which is more important? SBP vs. DBP5

A. Increase in SBP correlated with increase in mortality i. For every 10 mmHg increase, ~10% increase in stroke, CV events and death, and

all-cause mortalityii. Coronary events not significant

B. Relationship between DBP and mortality not significant i. Inversely correlated

ii. Increase in DBP trended towards decrease in all-cause (p=0.05) and CV deaths(p=0.08)

C. Conclusion i. Lowering of SBP most associated with decreased mortality and stroke, but not

coronary eventsii. Greatest absolute benefit seen in males, age ≥70 years, and prior CV events

I. J-curve association9-11 A. Paradoxical increase in mortality with decrease in blood pressure

i. Increase in cardiac events with lower DBPii. No association seen with stroke

iii. Meta-analysis showed increased benefit of reductions to at least 115/75mmHgB. Theories

i. Decreased vital organ perfusionii. Represents advanced vascular disease

iii. Product of another chronic disease

Figure 3. Example of J-curve11

THE LOWER THE BETTER?

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II. Falls12 A. Pathophysiology

i. Age related inability to compensate to maintain adequate blood perfusion to brain with change of position

ii. Further impairment by prolonged CV disease B. Incidence

i. Approximately 33% of those ≥65 years ii. Rises to 50% at ≥85 years

C. Hip fractures i. Mortality

a. In first year from home: 33% b. In first three months from nursing home: 33% c. In first year from nursing home: 50%

ii. Survivors: 66% have decreased mobility and 50% have chronic pain iii. Emotional iv. Recent meta-analysis showed no increase in falls with anti-hypertensives13

a. Decreased risk with prolonged treatment b. Increased risk with initiation

III. Polypharmacy14-15 A. Definition

i. Any medication without a clinical indication ii. Estimated that 58.6% take at least one unnecessary medication

iii. Generally considered five or more medications a. Over 37% of men and 36% of women aged 75+ b. Almost 46% of those ≥65 years of age take more than six unique

medications yearly B. Consequences

i. Increase of 30% in healthcare cost ii. Increased adverse events

a. Over four million medical visits related to adverse event reported in 2005

b. Incidence in elderly: 35% in outpatient and 40% inpatient c. Increase of 88% in risk of adverse event with five or more medications

iii. Drug interactions iv. Medication non-adherence v. Diminished functional status/cognitive impairment

a. Five or more medications: 22% b. Ten or more medications: 54%

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WHAT IS THE CURRENT EVIDENCE?

Table 3. Summary of Current Guidelines General Diabetics Elderly

JNC 8 Panel (2014)16

140[E]/90[A,High] <140/90[E] ≥60 years: <150/90[A, Mod-High]

ASH/ISH (2013)3

140/90 <140/90 ≥80 years: <150/90

ACC/AHA (2013)17

<140/90 <140/90 ≥80 years: <150/90

VA/DoD (2014)18

<150[Weak]/90 [Strong]

All ages: <150/85 [Strong] SBP <140 if tolerated [Weak]

≥60 years: <150/90[Strong]

ESH/ESC (2013)19

<140[1,B]/90[1,A] <140/85[1,A] ≥80 years: 150/90 [1,A] If “healthy” SBP <140 [IIB,C]

CHEP (2014)20

140[C]/90[A] <130[C]/80[A] ≥80 years: <150[C]/NA

NICE(2011)21 140/90 Unspecified ≥80 years: <150/90 ADA (2015)22 <140[A]/90[A]

<130[C]/80[B] may be appropriate if can be achieved without undue treatment burden

AGS (2013)23 <140/90 Potential harm with <120

WHAT SHOULD THE GOAL BE?

I. Oldest of the old: over 80 years of age A. Most guidelines in agreement for <150/90 mmHg for elderly (see Table 3)3,17,19-21,23 B. Poor prognosis seen with SBP <140 mmHg24

i. Increased all-cause mortalityii. Seen even after adjustment for age, sex, functional status, dementia, cancer and

CV diseaseiii. Low BP seen as marker of approaching frailty or imminent deathiv. Cardiac failure more common in SBP <140 mmHgv. Mean SBP lower with history of MI or stroke

Table 4. Mortality Stratified by SBP24 SBP, mmHg Total, n Deceased, n Mortality/1,000

person years Odds Ratio (95%

CI) Total 134 124 259.2 - <140 26 26 500.7 1.87(1.13-3.08)

140-159 39 37 268.3 -

160 69 61 211.4 0.79(0.52-1.18)

C. Benefit with goal of <150/80 mmHg25 i. Population

a. Total of 3,845 patients ≥80 years of ageb. With DM: 7%

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ii. Intervention a. Indapamide ± perindopril vs placebo b. Goal BP <150/80 mmHg achieved in 20% of placebo and 48% active

treatment iii. Results

a. Statistically significant decrease in overall mortality and HF b. Non-statistically significant decrease in stroke, death from CV cause and

death from stroke D. Changes as we age12,26

i. Change in CV hazard ratio a. For age >65 increases with SBP >140 b. For age >75 increases with SBP >150

ii. Stroke reduction decreases with age a. Aged 50-59: ↓62% b. Aged 80-89: ↓33%

E. Clinical Recommendations i. Goal SBP <150 mmHg

a. Due to frailty and limited lifespan, recommend regardless of presence of DM

b. Clear CV benefit seen in HYVET trial c. SBP <140 mmHg may be associated with increased mortality d. Desire to avoid initiation of medications due to risk of falls

ii. Goal DBP <90 mmHg a. Excluded from HOT trial b. No current evidence to support DBP <80 mmHg

iii. May consider SBP <140 mmHg a. Can be tolerated with no adverse events b. No fall risk c. High stroke risk

II. The middle men: 60-79 years A. Inconsistent

i. JNC 8 and VA/DoD raised goal to 150/90 mmHg for those 60 years ii. Remaining recommendations remain consistent with those <60 years

iii. Not all guidelines differentiate if age or DM take priority in BP goal B. JNC 8 dispute27

i. Consensus statement from an expert panel ii. Recommendation to raise goal to 150/90 mmHg not unanimous

iii. Minority view a. Strong support that SBP >150 mmHg has increased CV risk b. Insufficient evidence to raise BP goal from present 140 mmHg

C. Remaining thoughts/questions i. Not all answers may be found in randomized controlled trials

ii. Are we too strict with our blood pressure treatment in elderly diabetics? iii. Is age or presence of DM primary determinant of goal?

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LITERATURE REVIEW

Ogihara T, et al. Target blood pressure for treatment of isolated systolic hypertension in the elderly: valsartan in elderly isolated systolic hypertension study (VALISH). Hypertension. 2010;56:196-202.28

Purpose To determine if strict BP control (<140 mmHg) is superior to moderate BP control (140 mmHg to 149 mmHg) in reducing CV morbidity and mortality

Design Multicenter, parallel-group, prospective, randomized, open-label, blinded end point study conducted in Japan

Population Inclusion 70-84 years of age with primary

isolated systolic hypertension (SBP>160 mmHg and DBP <90 mmHg)

Exclusion SBP 200 mmHg or DBP 90 mmHg Stroke or MI in prior 6 months Severe HF (NYHA III and IV) Atrial fibrillation Renal dysfunction (SCr 2 mg/dl)

Outcomes Primary: composite of the following CV events: sudden death, fatal or nonfatalstroke, fatal or nonfatal MI, HF or other CV related death, hospitalization for CVdisease and renal dysfunction

Secondary: each component of primary end point, total mortality, new onset orexacerbation of angina, and adverse events

Methods Patients randomized to achieve SBP goal of either <140 or 140 mmHg to 149mmHg

Valsartan titrated to ≤160mg was initial therapy followed by any additionalanti-hypertensive therapy necessary to achieve BP target

Patients visited clinic every 3 months for minimum of 2 years Investigators asked to complete case report forms to document endpoints

Results Baseline characteristics not significantly different except for smoker ratio(strict: 21% vs moderate: 17.4%)

Median follow-up 3.07 years

Strict (N=1545) Moderate (N=1534) p-value (<0.05)

Mean BP, mmHg 136.6/74.8 142.0/76.5 Primary endpoint 47(3.04%) 52(3.39%) 0.383

All-cause mortality 24(1.55%) 30(1.96%) 0.78 CV death 11(0.71%) 11(0.72%) 0.97

Fatal and non-fatal stroke 16(1.04%) 23(1.50%) 0.68 Fatal and non-fatal MI 5(0.32%) 4(0.26%) 1.23

Renal insufficiency 5(0.32%) 2(0.13%) 2.45 Diabetes present Primary endpoint

211 8.06%

188 7.45% 0.737

Adverse Events* 18.2% 17.9% 0.851 *Most were gastrointestional or respiratory symptoms

Conclusion Strict BP control may not offer any additional CV event benefit over moderatecontrol

Blood pressure targets of <140 mmHg are safely achievable in relatively

healthy patients 70 years of age

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Critique Strengths Prospective, randomized trial Only elderly included SBP targets as primary endpoint Reported adverse effects Separate DM analysis

Limitations Underpowered to determine

superiority “Healthier”: 5% with CAD Small diabetes population Short follow-up period

Take Home Points

No increase in adverse effects with SBP <140 compared to 140 to 149 mmHg in relatively healthy patients aged 70-84 years

Superior SBP goal for CV morbidity and mortality unclear CV=Cardiovascular; MI=Myocardial Infarction; HF=Heart Failure; NYHA=New York Heart Association; CAD=coronary artery disease

Bangalore S, et al. 2014 Eighth Joint National Committee panel recommendation for blood pressure targets revisited: results from the INVEST study. J Am Coll Cardio. 2014;64:784-93.29

Purpose To establish the optimal blood pressure target for patients >60 years of age with coronary artery disease (CAD)

Design Prospective, randomized, blinded-endpoint trial conducted in 14 countries Non-pre-specified post-hoc analysis

Population Inclusion 60 years of age Documented CAD Baseline SBP ≥150 mmHg

Exclusion Unstable angina Angioplasty, CABG, or stroke in

prior month Severe HF: NYHA IV Severe renal (SCr ≥4.0) or hepatic

failure Outcomes Primary: first occurrence of all-cause death, nonfatal MI, or nonfatal stroke

Secondary: all-cause mortality, CV mortality, total MI, nonfatal MI, total stroke, nonfatal stroke, heart failure, and revascularization

Methods Randomized to either atenolol/hydrochlorothiazide or verapamil sustained release/trandolapril

Blood pressure was titrated to <140/90 mmHg or <130/85 mmHg in presence of DM or CKD (per JNC 5/6 guidelines)

Categorized based on achieved on-treatment SBP after 2 years: <140 mmHg, 140 to 149 mmHg, and 150 mmHg

Multiple propensity score adjustment for differences in baseline characteristics Results

N=8,354 o DM 29%

No significant baseline differences after multiple propensity score adjustment Unadjusted outcomes

o SBP <140 mmHg had lowest rate of primary outcome, all-cause mortality, CV mortality, total MI, nonfatal MI, total stroke, and nonfatal stroke

Multiple propensity score-adjusted model SBP <140 mmHg had lowest rate of CV mortality, total stroke, and nonfatal

stroke compared to <150 mmHg

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Results Traditional Cox Proportional Hazards Regression Model <140 mmHg 140 to <149 mmHg 150 mmHg

Primary Outcome

1.00 1.09 (0.93-1.29) p=0.27

1.82(1.58-2.09) p<0.0001

All-cause mortality

1.00 1.00(0.83-1.20) p=0.99

1.60(1.37-1.86) p<0.0001

CV mortality 1.00 1.31(1.00-1.73) p=0.05

2.18(1.73-2.76) p<0.0001

Total MI 1.00 1.14(0.87-1.51) p=0.34

2.23(1.78-2.81) p<0.0001

Total Stroke 1.00 1.88(1.27-2.78) p=0.002

2.83(1.98-4.04) p<0.0001

Adverse Effect (%)

<140 mmHg 140 to 149 mmHg 150 mmHg p value

Angina 3.9 6.2 4.4 0.0004 Dizziness 2.3 3.9 4.4 <0.0001 Dyspnea 1.6 2.6 2.2 0.03 Headache 0.8 1.9 1.8 0.0001 Lightheadedness 0.8 1.5 1.6 0.0027 Symptomatic bradycardia

1.73 2.6 3.6 <0.0001

Conclusion In patients 60 years of age with CAD, a SBP of <140 mmHg is associated with numerically the lowest rate of several CV morbidity and mortality measures

Critique Strengths Large DM population All patients 60 years of age High risk population Evaluated several adverse effects

Limitations Not designed to test BP goals Not randomized for outcomes No separate DM analysis Short follow-up time

Take Home Points

Patients 60 years of age with CAD may benefit equally from SBP <140 mmHg and 140-149 mmHg in CV morbidity and MI, but patients with SBP 140-149 mmHg may be at increased risk of stroke

Patients with SBP <140 had the lowest rate of several adverse effects CABG=coronary artery bypass graft; CKD=chronic kidney disease

Sim JJ, et al. Impact of achieved blood pressures on mortality risk and end-stage renal disease among a large, diverse hypertension population. J Am Coll Cardio. 2014;64:588-97.30

Purpose To evaluate the risk of mortality and/or end-stage renal disease (ESRD) across various blood pressure ranges

Design Retrospective cohort study within the Kaiser Permanente Southern California (KPSC) health system

January 1, 2006 to December 31, 2010 Population Inclusion

18 years of age Diagnosis of hypertension Prescription for anti-hypertensive

Exclusion Dialysis or renal transplant Heart failure

Outcomes Primary: composite of all-cause mortality or ESRD Secondary: all-cause mortality, ESRD, +/- DM, <70 or 70 years of age

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Methods Subjects were identified through the KPSC electronic medical record by containing 2 International Classifications of Disease-Ninth Revision (ICD-9) codes specific to hypertension.

Baseline and all subsequent blood pressures were collected Blood pressure ranges of 130-139/80-89 mmHg were used as reference ranges

Results N=398,419 (DM~33%) Mean follow-up 4.0 years; Median 4.5 years Statistically significant baseline characteristics (p-value <0.001)

Age Sex CKD Cerebrovascular disease Creatinine eGFR Race DM Ischemic heart disease For the primary analysis including all patients SBP 130-139 had best outcomes

SBP, mmHg Adjusted HR

w/ DM 95% CI Adjusted HR

70 years 95% CI

<110 3.50 3.20-3.82 4.13 3.86-4.42 110-119 1.43 1.35-1.52 1.90 1.81-1.99 120-129 0.97 0.92-1.02 1.19 1.14-1.24 130-139 - - - - 140-149 1.68 1.58-1.78 1.33 1.27-1.39 150-159 2.82 2.59-3.04 2.56 2.28-2.86 160-169 4.38 3.89-4.93 3.46 3.00-3.98

DBP, mmHg Adjusted HR 95% CI

<50 3.14 2.73-3.61 50-59 0.96 0.91-1.02 60-69 0.72 0.69-0.76 70-79 0.70 0.67-0.73 80-89 - - 90-99 1.92 1.73-2.13

100 3.83 3.04-4.83

Nadir for lowest risk of mortality and ESRD o All: 137/71 mmHg o DM: 131/69 mmHg o 70 years of age: 140/70

Conclusion HTN patients with SBP of 130-139 mmHg and DBP of 60-79 mmHg had the lowest risk of mortality and ESRD

Critique Strengths Separate analysis of a large DM and

70 years of age population System-wide HTN treatment

protocol (Appendix 2) Wide range of SBP and DBP studied Longer follow-up time

Limitations Observational, retrospective Several statistically significant

differences at baseline Unknown pleotropic effects of other

medications No adverse effects reported

Take Home Points

Mortality and ESRD benefit overlap for DM and patients 70 years of age at a SBP range of 130-139 mmHg

DBP has a wider acceptable range of benefit from 60-79 mmHg. DM and 70 years of age benefited most at DBP of 69 and 70 mmHg, respectively

CI=confidence interval

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Liu L, et al. The felodipine event reduction (FEVER) study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005;23:2157-72.31

Purpose To assess the incidence of cardiovascular events between the treatment blood pressures of a diuretic and calcium channel antagonist combination and diuretic monotherapy.

Design Multicenter, prospective, double-blind, randomized, placebo-controlled, parallel group trial conducted among 109 hospitals and clinics in China

Population Inclusion Aged 50-79 years SBP 210 mmHg and DBP

<115mmHg if treated SBP 160-210 mmHg or DBP 95-

115mmHg if untreated If 60 years of age, were required to

have clinical evidence or history of a CV event or presence of at least 2 CV risk factors*

If >60 years of age, required to have one event or one risk factor*

Exclusion Stroke or MI in previous 6 months Secondary HTN Unstable angina SCr >2.0 mg/dl Uncontrolled DM (fasting BG >180

mg/dl despite therapy)

Outcomes Primary: time to first fatal and nonfatal stroke Secondary: all CV events + composite of various CV outcomes, death from any

cause Methods Open label hydrochlorathiazide 12.5mg daily for 6 weeks

Randomized to: o Hydrochlorathiazide+ felodipine 5mg daily o Hydrochlorathiazide + placebo

If BP>160/95 mmHg on two consecutive visits, could receive additional HCTZ 12.5mg and any other non-calcium channel antagonist antihypertensive agent

Results Mean follow-up time: 40 months Felodipine (%)

N=4841 Placebo (%)

N=4870 HR (95% CI) p-value

BP, mmHg 137.3/82.5 142.5/84.0 Stroke 177(3.7) 251(5.2) 0.73(0.60-0.89) 0.0019

All CV events 241(5.0) 334(6.9) 0.73(0.61-0.86) 0.0002 All-cause death 112(2.3) 151(3.1) 0.69(0.54-0.89) 0.0053

CV death 73(1.5) 101(2.1) 0.67(0.48-0.91) 0.0112 Heart Failure 18(0.4) 27(0.6) 0.70(0.37-1.30) 0.2604 Renal failure 10(0.2) 8(0.16) 1.38(0.54-3.52) 0.4994

DM: ~13%(n=1241) Mean difference in BP: 4/2 mmHg Adverse events (AE)

o Felodipine group had more flushing and ankle edema o Similar incidences of dizziness, headache, fatigue and palpitations

Conclusion A decrease in BP as small as 4/2 mmHg can provide substantial decreases in risk of cardiovascular outcomes

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Critique Strengths Randomized, double-blinded Add-on therapy and other

pleotropic medications assessed Only elderly included Reported AE

Limitations Short follow up time No separate analysis of only DM

patients May not be applicable to US

population

Take Home Points

A SBP <140 mmHg was shown superior to <150 mmHg in decreasing risk of stroke,

CV events, and death in this population of patients 60 years of age that included DM patients.

*male sex, current smoking of more than one cigarette per day during at least 1 year, total serum cholesterol ≥220 mg/dl within the previous year or lipid-lowering treatment, diabetes mellitus, left ventricular hypertrophy, proteinuria, body mass index >27 kg/m2

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SUMMARY I. Limited support for SBP <140 mmHg

A. Most high level evidence trials only compared treatment <150 mmHg vs no treatment B. CV differences

i. Most studies show no difference in CV events or death ii. Majority show decrease risk of stroke

C. Adverse effects i. Little to no risk of increased adverse effects

ii. Some data to support decrease in adverse effects II. Wider acceptable DBP range

A. Limited trials with DBP goals as endpoints i. Most support for <80 mmHg is result of HOT trial

a. Mean DBP achieved 81 vs 85 mmHg b. Only significant in DM population of ~1,500 patients

ii. Analysis showed 60-79 mmHg had greatest benefit iii. Difficult to distinguish effect of SBP from DBP iv. DBP not as important for CV benefit

III. Relationship between BP and risk A. Linear for stroke risk B. U or J shaped for cardiovascular

CLINICAL RECOMMENDATIONS

I. Patients 80 years of age A. Goal <150/90 mmHg

i. Due to frailty and limited lifespan, recommend regardless of presence of DM ii. Excluded from VALISH and FEVER

iii. Increased mortality shown with >85 years iv. Less stroke benefit achieved with treatment v. Avoidance of drug initiation due to increased risk of falls

B. May consider <140/90 mmHg i. “Physically fit”

ii. High stroke risk II. Patients 60-79 years of age

A. Primary target of SBP <140 mmHg i. Most important in those at increased risk of stroke

ii. Though conflicting, may provide benefit over SBP <150 mmHg iii. Limited negative consequences seen in trials iv. If very frail, may use target of <150 mmHg

B. DBP goal uncertain i. Insufficient RCT to show <80 mmHg superior to <90 mmHg

ii. No current evidence shows one more harmful in CV events or adverse effects iii. Although not a primary endpoint, most studies achieved a DBP <80 mmHg iv. Recommend DBP goal <80 mmHg if can be reached without undue harm to

patient v. Recommend DBP goal <90 mmHg if very frail or AE present at <80 mmHg

III. Patient specific A. Patient’s preference for more or less aggressive treatment B. Values on falls vs CV benefit C. Treat based on “physiological” age instead of chronological

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Appendix A. Summary of Trials with Elderly Diabetics Trial Participants Intervention Outcomes Take Away Supporting SBP <150 mmHg SHEP32 (1991) N=4736

(12.3% DM) Age ≥60 years

If SBP >180, goal: SBP <160; If SBP 160-179, goal SBP ↓20 mmHg vs placebo

Mean achieved BP: 143/68 vs 155/72 ↓36% stroke (p=0.0003)

BP <145/70 improved outcomes compared to <155/75

Syst-Eur33 (1997) N=4695 (10.5% DM) Age ≥60 years

SBP <150 mmHg vs placebo ↓42% stroke (p=0.0003) ↓26% all cardiac endpoints (p=0.03)

Treating to SBP <150 provides CV protection

Syst-China7 (2000) N=2394 (4.1% DM) Age ≥60 years

SBP <150 mmHg vs placebo ↓38% stroke

↓37% CV events

↓39% mortality

Treating to SBP <150 provides CV protection

UKPDS 3834 (1998) N=1148 (100% DM) Age: 25-65 years

<150/85 mmHg vs. <180/105 mmHg

Mean achieved BP: 144/82 vs 154/87 ↓32% mortality (p=0.019) ↓21% MI (NS) ↓44% stroke (p=0.013) ↓37% microvascular (p=0.0092)

Mean BP of <145/85 superior to <155/90

Supporting SBP <140 mmHg ALLHAT35 (2000) N=24316

(DM=43%) Age >55 years

Doxazosin vs chlorthalidone

Mean achieved BP: DM: 137/75 vs 136/75 nonDM: 137/77 vs 135/77

BP reduction to <140/80 had CV benefit

ADVANCE36 (2007)

N=11,140 DM=100% Age >55

Perindopril+indapamide vs placebo

Achieved BP: 139.4/78.8 ↓9% macrovascular+ microvascular (p=0.04) ↓18% CV mortality (p=0.03)

BP of <140/80 showed CV benefit compared to placebo

ACCORD37

(2010) N=4733 DM=100% Age >40 years

SBP <120 mmHg vs <140 mmHg

Mean SBP achieved: 119.3 vs 133. CV events: 1.87% vs 2.9% (NS) All-cause mortality: 1.28% vs 1.19% (NS) Stroke: 0.32% vs 0.53% (p=0.01) Adverse effects: 3.3% vs 1.3% (p<0.001)

No additional CV benefit, but decreased stroke in <120 vs <140 ↑AE with goal 120

Supporting DBP goals HOT38

(1998) N=18,790 DM=1,501 (8%) Age 50-80 years

DBP goals of <90 vs <85 vs <80 mmHg

Achieved DBP: 85.2 vs 83.2 vs 81.1 DM: ↓51% in CV events in <80 vs <90 (p=0.005)

Primary trial cited to support DBP <80 mmHg, but most patients did not reach goal.

DM=Diabetes Mellitus; NS=Nonsignificant ; BP=blood pressure, SBP=systolic blood pressure; DBP=diastolic blood pressure; AE=adverse events

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Appendix B. Kaiser Permanente Southern California Hypertension Algorthim29