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CARDIOLOGY AND THE OLDER ADULTKristin Zimmerman, PharmD, CGP, BCACP

Associate Professor, GeriatricsDepartment of Pharmacotherapy & Outcomes Science

VCU School of Pharmacy

DISCLOSURES

• Spouse employed by Biogen, Inc.

• No relevance to the content of this presentation.

LEARNING OBJECTIVESAT THE CONCLUSION OF THIS APPLICATION-BASED ACTIVITY, PARTICIPANTS

SHOULD BE ABLE TO:

1. Interpret recent guidelines and clinical data regarding the management of dyslipidemia, hypertension, stroke prophylaxis in patients with atrial fibrillation, and dual antiplatelet therapy

2. Select appropriate treatment goals for older adults with hypertension and dyslipidemia.

3. Examine the impact of common adverse effects observed with cardiovascular pharmacotherapy in the older adult.

4. Evaluate the potential role of emerging and recently approved therapies.

DYSLIPIDEMIA

A Tale of Two Approaches

2013 ACC/AHA Guidelines

2014 National Lipid Association

2013 ACC/AHA LIPID GUIDELINES

• True or False?– Recommended against goals of therapy.– Recommended less lipid panel monitoring.– Provided guidance on managing hypertriglyceridemia,

patients with metabolic syndrome, and special populations (e.g., HIV).

– Have been well received and widely adopted in clinical practice.

2013 ACC/AHA GUIDELINES: FOUR STATIN BENEFIT GROUPS

Benefit Group Therapy

1Clinical ASCVD (MI, angina, stroke, TIA, PAD)

High intensity statin2 LDL-C ≥190 mg/dL (≥ 5 mmol/L)

3 Diabetes (Age 40-75)10-y risk ≥7.5% *

10-y risk <7.5% Moderate intensity statin

*moderate to high intensity4 10-y risk ≥7.5% (Age 40-75)*

ASCVD: atherosclerotic cardiovascular diseaseStone NJ, et al. Circulation. 2014;129:S1-S45.

STATIN DOSE INTENSITIES

Atorvastatin 10 mg; 20 mgRosuvastatin 5 mg; 10 mgSimvastatin 20 mg; 40 mg

Lovastatin 40 mgPravastatin 40 mg; 80 mg

Atorvastatin 40 mg; 80 mgRosuvastatin 20 mg; 40 mg

High-intensity(LDL-C reduction ≥ 50%)

Moderate-intensity(LDL-C reduction 30 to <50%)

“The panel makes no recommendation for or against specific LDL-C or Non-HDL-C targets for primary or secondary prevention of ASCVD.”

Stone NJ, et al. Circulation. 2014;129:S1-S45.

NLA STEPS IN ASCVD RISK ASSESSMENT

• ASCVD

• Diabetes with ≥2 other major ASCVD risk factors or end organ damage1) VERY HIGH risk conditions?

• Diabetes with 0-1 other major ASCVD risk factors

• Chronic kidney disease Stage 3 or 4

• LDL-C ≥190 mg/dL2) HIGH risk conditions?

• ASCVD Risk Factors (FLASH): Family history; Low HDL-C; Age; Smoking; Hypertension

3) Count major ASCVD risk factors

• If 0-1 and no other indicators of higher risk: low risk

• If 2, risk scoring is recommended consider additional testing

• If ≥3 major ASCVD risk factors: high risk

• Framingham: If >10% 10-year hard CHD risk: high risk

• ASCVD: If ≥15% 10-year hard CHD risk: high risk

• Otherwise, assign to moderate risk category

4) Risk scoring (Framingham or ASCVD)

Jacobson TA et al. J Clin Lipid. 2014;8:473-488.

3) Count major ASCVD risk factors

NLA RISK ASSESSMENT AND TREATMENT GOALSRisk Group

Non-HDL-C

mg/dL (mmol/L)

LDL-C

mg/dL (mmol/L)

ApoBmg/dL (g/L)

VERY HIGH RISK • ASCVD (Clinical Atherosclerosis)

• Diabetes mellitus (type 1 or 2) AND

• >2 other major ASCVD risk factors(s) OR

• Evidence of end-organ damage

<100(2.6)

<70(1.8)

<80(0.8)

HIGH RISK • >3 major ASCVD risk factors

• Diabetes mellitus (type 1 or 2) AND

• 0-1 other major ASCVD risk factors, AND

• No evidence of end-organ damage

• Chronic kidney disease Stage 3 or 4

• LDL-C >190 mg/dL (≥ 5 mmol/L )

• FRS >10% 10-year, ASCVD > 15% hard CHD event risk

<130(3.4)

<100(2.6)

<90(0.9)

MODERATE RISK • 2 ASCVD risk factors

• Quantitative risk scoring recommended

• Consider other risk indicators

<130(3.4)

<100(2.6)

<90(0.9)

LOW RISK • 0-1 major ASCVD risk factors

• Consider other risk indicators, if known

<130(3.4)

<100(2.6)

<90(0.9)

J Clin Lipid. 2014;8:473-488

WHICH RISK SCORE IS BEST?

Risk Calculator Endorsement Outcome

Framingham Risk Calculatorcvdrisk.nhlbi.nih.gov/

ATP III, NLA, Canadian Cardiovascular Society

10-year risk of MI or death

ASCVD Pooled Risk Calculatortools.cardiosource.org/ASCVD-Risk-Estimator/

ACC/AHA 10-year ASCVD risk and lifetime ASCVD risk

Cardiovascular Age https://myhealthcheckup.com

Canadian Cardiovascular Society

Cardiovascular age equivalent

THE TALE OF TWO APPROACHES

Statins are the most potent and evidence-based approach to lower atherogenic lipoproteins and reduce ASCVD risk

Patients at high risk benefit from high-intensity statins

ACC/AHA 2013 NLA 2014

“Lower is better”Benefit derived from statin presence rather than target lipoprotein levels

Stone NJ, et al. Circulation. 2014;129:S1-S45.Jacobson TA et al. J Clin Lipid. 2014;8:473-488.

11

1,500

1,000

500

00 50 100 150 200 250

Mean = 696,217St. Dev. = 26.95N=18,661

Freq

uen

cy

LDL-C (mg/dL)

Boekholdt SM, et al. J Am Coll Cardiol. 2014;64:485-494.

• Meta-analysis of 8 RCT with statins• 38,153 subjects • 6,286 major CV events in 5,387 patients

LDL-C VARIABILITY AMONG INDIVIDUALS ON

HIGH-INTENSITY STATINS

40% did not achieve LDL-C <70 mg/dL (1.8 mmol/L) on Atorvastatin 80 or Rosuvastatin 20 mg daily

http://cvdrisk.nhlbi.nih.gov/

http://tools.cardiosource.org/ASCVD-Risk-Estimator/

https://myhealthcheckup.com/

LDL-C VARIABILITY BY STATIN

Pitavastatin

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

0

10

20

30

40

50

60

0 mg 10 mg 20 mg 40 mg 80 mg

LD

L R

ed

uc

tio

n (

%)

Dose

Average LDL cholesterol reduction in patients with primary hypercholesterolemia on monotherapy based Food and Drug Administration product labeling for each compound.

Increasing risk of myositis

Pitavastatin1 mg 2 mg 4 mg

Jones P, et al. Am J Cardiol 2003;92:152-160

RESIDUAL RISK DESPITE STATIN THERAPY

-34%

-24%

-37%

-24%-29%

-24%

-15%

-37% -36%

-60%

-50%

-40%

-30%

-20%

-10%

0%

Re

lati

ve R

isk

Re

du

ctio

n

Available at: www.medscape.org/viewarticle/569095

Despite the benefits of LDL-C lowering, 60% to 80% residual risk remains.

Simvastatin Pravastatin AtorvastatinLovastatin

DYSLIPIDEMIA

Focus on Older Adults

NLA RECOMMENDATIONS FOR SPECIAL

GROUPS: OLDER PATIENTS

• Use risk calculators cautiously!

• Options for older adults with statin intolerance:

– Low-intensity statin therapy

– Non-daily moderate intensity statin therapy

– Low-intensity statin + ezetimibe or BAS

– Ezetimibe or BAS

Aim to decrease LDL-C by

>30%

NLA Recommendations Part 2. Available at: https://www.lipid.org/recommendations. Accessed 7/8/2015.

TOO OLD FOR SECONDARY PREVENTION? Trial Intervention Age Subgroup (n) Outcomes

Seco

nd

ary

Pre

ven

tio

n

SPARCL A80 vs PLMean age ~63(4731)

“No heterogeneity” (no difference) between <65/65+ NS stroke reduction; Combined stroke*/TIA, CHD events, revasc.

4S S20-40 vs PL 65-70 (1021) all-cause death, CHD death, CHD events

LIPID P40 vs PL 65-75 (3514) all-cause death, CHD deaths, CHD events, stroke

CARE P40 vs PL 65-75 (1283) CHD death, CHD events, stroke

HPS S40 vs PL 70-80 *5806) CHD events

PROSPER P40 vs PL 70-82 (5804) CHD death, CHD events

PROVE-IT TIMI 22 A80 vs P40 >70 (534) CHD events

TNT A80 vs A10 65-75 (3809) CHD events, stroke

SAGE A80 vs P40 65-85 (893) all-cause death, CHD death, CHD events

Meta-Analysis 65-82 (19569) all-cause death, CHD deaths, CHD events, stroke

TOO OLD FOR PRIMARY PREVENTION?Trial Intervention Age Subgroup (n) Outcomes

Pri

mar

y P

reve

nti

on

PROSPER P40 vs PL 70-82 (5804) Non-significant in post-hoc analysis

Meta Analysis(BMJ)

Mean age ~63 (7038)

“No heterogeneity” (difference) between <65/65+Possible benefits on major CVD & CVA events in >65 (underpowered)

Meta Analysis (CTT)

Mean age 74 (104356)

No difference in major CVD events in <65, 65-75 & 75+

http://www.medscape.org/viewarticle/569095

ALLHAT-LLA• Post-hoc secondary analysis of older adults

– Pravastatin 40mg versus “USUAL CARE”• ”treated for LDL-C level lowering based on the discretion of their primary care physician”

– 65 and older, stage 1-2 HTN, 1 CVD risk factor, no baseline ASCVD– All cause mortality not different (HR 1.18, 0.97-1.42 p = 0.09)

• 65-75 years: HR 1.08, 0.85-1.37 p = 0.55• 75+ years: HR 1.34, 0.98-1.84 p = 0.07

– LIMITATIONS:• 29% of usual care received a statin• 22.2% of pravastatin users stopped statin

– Does NOT answer questions of statin continuance– Does it answer whether to start a statin?

STAREE TRIAL

• Clinical trial of statin therapy for reducing events in the elderly– 70 years or older, community dwelling, no ASCVD,

DM, or lipid lowering therapy– Atorvastatin 40mg versus placebo– Time to death, dementia, disability, major fatal or

nonfatal event– Data collection to finish in 2020

PATIENT CASE: POLL #1• Mr. ST is an 89 yo African-American

male living independently. He has HTN and had an MI at age 70. Recently, he’s experienced chest pain with exertion that’s worsened over the past year.

• Medications:– Aspirin 81mg daily– Metoprolol succinate 50mg daily– Isosorbide mononitrate 60mg daily– Furosemide 40mg daily– SL NTG 0.4mg as needed

• He presents to his PCP for a checkup to review labs drawn the day before:

– TC 168 mg/dL ( 4.3 mmol/L)– LDL-C 105 mg/dL (2.7 mmol/L)– HDL-C 41 mg/dL (1.1 mmol/L)– TG 109 mg/dL (1.2 mmol/L)

Which of the following would be the most appropriate action to take regarding the initiation of statin therapy?A. Statin therapy not indicated due to age.B. Statin therapy not indicated due to patient

being at low risk.C. Initiate moderate-intensity statin therapy.D. Initiate high-intensity statin therapy.

HOW OLD IS TOO OLD FOR STATIN THERAPY?

Age 65-79 years treat with moderate or high-intensity statin as indicated by

ASCVD risk

Age >75 years Or with conditions influencing statin therapy moderate

intensity statin


Provider-patient discussion should consider drug-drug interactions, polypharmacy, concomitant medical conditions including frailty, cost considerations, and patient preference.


Age <75 years without contraindications high-intensity statins

Age >80 with ASCVD consider moderate intensity statin after provider-

patient discussion

SUGGESTED ALGORITHM: OLDEST-OLD

Strandberg TE, Kolehmainen L, Vuorio A. Evaluation and Treatment of Older Persons with Hypercholesterolemia: A Clinical Review. JAMA (2014): 312(11): 1136-44.

STATIN IN ADVANCED, LIFE-LIMITING ILLNESS?• Life expectancy of 1

month to 1 year

• On a statin >3 months

– Time to death + 1st CV event within 60 days

– Non-inferiority hypothesis

VariableDiscontinued

Statin (n=189), No. (%)

Continued Statin (=192) No. (%)

Age, mean (SD), y 74.8 (11.7) 73.5 (11.5)

Female 91 (48.1) 80 (41.7)

White 153 (81.0) 162 (84.4)

History of CVD 111 (58.7) 110 (57.3)

Statin use >5 years 129 (68.3) 134 (69.8)

Primary diagnosis• Malignant

tumor84 (44.4) 102 (53.1)

Cognitively impaired 51 (27.0) 33 (17.2)

STATIN IN ADVANCED, LIFE-LIMITING ILLNESS?• Noninferiority NOT achieved • Survival was similar between the two groups (p=0.60)• No difference in time to first CV event (p=0.64)• McGill QOL was higher among those who discontinued

statin therapy (p=0.04)• Cost savings per participant was $716 over a 212 day

follow-up– Projected savings in 2014 $604 million

Kutner JS, et al. JAMA Intern Med. 2015;175(5):691-700.

STATINS AND DIABETES RISK?

Characteristic 0 risk factors (n=6,095)>1 risk factors

(n=11,508)P

Age (years) 66 66 0.37

Women 1,963 (32%) 4,771 (41%) <0.0001

LDL-C (mg/dL) 108.3 109 0.001

HDL-C (mg/dL) 54 46 <0.0001

TG (mg/dL) 97.4 133.7 <0.0001

TC (mg/dL) 184.4 186.4 0.001

Plasma glucose (mg/dL) 89 98.9 <0.0001

A1C (%) 5.6 5.8 0.001

BMI (kg/m2) 25.4 30.7 <0.0001

Hypertension 2,757 (45%) 7,338 (64%) <0.0001

Ridker PM, et al. Lancet. 2012;380(9841):565-571.

Baseline Characteristics of JUPITER Patients by Major Diabetes Risk Factors

ROSUVASTATIN RISK REDUCTION: JUPITERRisk Benefit

No Major Diabetes Risk factor*

86 total CV events or deaths avoided with 0 new diabetes diagnoses

>1 Major Diabetes Risk factor*

134 total CV events or deaths avoided for every 54 new diabetes diagnoses

Risk of diabetes among statin-treated patients appears limited to those with baseline evidence of any of the following:

Impaired fasting glucose; Metabolic syndrome; BMI >30 kg/m2; or A1C >6%.

Ridker PM, et al. Lancet. 2012;380(9841):565-571.

INCIDENT DIABETES: INTENSIVE VERSUS

MODERATE-DOSE STATIN THERAPY

Preiss D. JAMA. 2011;305(24):2556-2564.

NNH498

NNT155

DYSLIPIDEMIA

Non-Statin Therapies

QUANTITATIVE EFFECTS ON LIPID PROFILE

Agents Lower

LDL-C

Raise

HDL-C

Lower VLDL-C

HMG-CoA Reductase Inhibitors (statins)

18-55% 5-15% 7-30%

PCSK9 Inhibitors 58% NR NR

Ezetimibe 18% 1% 7-9%

Bile acid sequestrants 15-30% 3-5% or

Niacin 5-25% 15-35% 20-50%

Fibric acid derivatives 5-20% 10-20% 20-50%

Omega 3 Fatty Acids (fish oil)

or 45% 9% 42%

Adapted from NCEP ATP-III Guidelines and product information.

IMPROVE-IT: EZETIMIBE + SIMVASTATIN VS. SIMVASTATIN

• 18,144 patients stabilized <10 days post ACS

• Mean age at baseline was 64 years

• Baseline LDL-C at time of ACS event was 95 mg/dL

• Primary composite endpoint:– CV death, MI, hospital admission for UA, revascularization, or stroke.

Lipid Measurement(1 Year Mean)

Ezetimibe/Simvamg/dL

Placebo/Simvamg/dL

Change in mg/dL (mmol/L)

HDL-C 48.7 48.1 mg/dL +0.6 (0.02)

Triglycerides 120.4 137.1 mg/dL -16.7 (0.19)

LDL-C 53.2 69.9 mg/dL -16.7 (0.43)

hs-CRP 3.3 3.8 mg/dL -0.5

IMPROVE-IT (TIMI 40) website. www.timi.org. Accessed 5/4/2015.

31

IMPROVE-IT: RESULTS


*7-year event rates (%) Risk ratio & 95% CI

HRSimva*EZ/Simva*

All-cause death 15.4 15.3 0.99 0.782

Cardiovascular disease 6.9 6.8

Coronary heart disease 5.7 5.8

1.00 0.997

13.1 14.8Myocardial Infarction

4.2 4.8

0.96 0.499

Stroke

3.4 4.1Ischemic Stroke

Revascularization 21.8 23.4

0.87 0.002

Unstable angina 2.1 1.9

20.4 22.2

1.0 1.4 0.6 EZ/Simva better Simva better

CVD/MI/Stroke

0.86

0.79

0.95

1.06

0.90

0.052

0.008

0.107

0.618

0.003

p-value


IMPROVE-IT: KEY ENDPOINTS IMPROVE-IT: SUBGROUPS AND SAFETY

• Patients >75 years of age (n=2798) experienced a 8.9% lower event rate in the EZ/Simva group compared to placebo/simvagroup (p=0.005)

• Patients with diabetes experienced a 5.5% lower event rate in the EZ/simva group compared to placebo/simva group (p=0.023)

No statistically significant difference in cancer or muscle- or gallbladder-related adverse events


34

PATIENT CASE: POLL #2• Ms. P is an unmarried 86 yo Caucasian

female living in a nursing home. She has HTN, hyperlipidemia, and carotid artery stenosis. She was also diagnosed with Alzheimer disease 3 years ago.

• MMSE score is 8 out of 30.• She requires 24-hour assistance.• 1-year mortality risk is 28%*

• Medications:– Simvastatin 20mg daily– Aspirin 81mg daily– Bisoprolol 5mg daily– Felodipine 5mg daily– Galantamine ER 24mg daily– Memantine 10mg q12 hours– Quetiapine 75mg daily– Lorazepam 1mg as needed– Pantoprazole 20mg daily– Calcium-vitamin D daily

Which of the following would be the most appropriate action to take regarding her statin therapy?A. Continue simvastatin 20mg daily.B. Change simvastatin to atorvastatin 40mg daily.C. Decrease simvastatin to 10mg daily.D. Discontinue simvastatin.

*Estimated Prognosis for Elders Score

PCSK9 INHIBITOR – MECHANISM OF ACTION

LDL-R

PCSK9

Lysosome

LDL-C

LDL-RRecycling

PCSK9 Inhibitor (mAb)

LDL-C

http://www.nature.com/nrd/journal/v11/n11/fig_tab/nrd3879_F1.html

http://www.nature.com/nrd/journal/v11/n11/fig_tab/nrd3879_F1.html

PCSK9-INHIBITORS

• Approved agents:– Alirocumab– Evolocumab

• Use– Adjunct therapy to diet and maximally tolerated statin/LDL-lowering therapy for patients with

heterozygous hypercholesterolemia, homozygous familial hypercholeserolemia (evolocumab) or history of ASCVD who require additional lowering of LDL-C (evolocumab)

• Additional place in therapy?– Statin intolerant patients– Not at treatment goals despite maximum, tolerated statin– Monotherapy in place of statin therapy???

Alirocumab (Praluent®). Package Insert. Accessed 7/29/15.McKenney JM. J Clin Lipidol. 2015; 9:170-186

LDL-C Non-HDL apo B

58% 50% 51%

EVOLOCUMAB: CARDIOVASCULAR OUTCOMES

• Atherosclerotic disease, LDL > 70 mg/dL (1.8 mmol/L), Taking statin therapy

• Evolocumab 140 mg SQ every 2 weeks or 420 mg SQ monthly versus matched placebo– Primary endpoint: composite of cardiovascular death, myocardial infarction,

stroke, hospitalization for unstable angina, or coronary revascularization. – Secondary end point: composite of cardiovascular death, myocardial

infarction, or stroke

• Median duration of follow-up was 2.2 years

Sabatine MS, et al. March 17, 2017, at NEJM.org..

EVOLOCUMAB: CARDIOVASCULAR OUTCOMES

Outcome Evolocumab(n = 13784)

Placebo(n = 13780)

HR(95% CI)

Primary: CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization

1344 (9.8) 1563 (11.3) 0.85 (0.79-0.92)

Secondary: CV death, MI or stroke 816 (5.9) 1013 (7.4) 0.80 (0.73-0.88)

CV death 251 (1.8) 240 (1.7) 1.05 (0.88-1.25)

Death from any cause 444 (3.2) 426 (3.1) 1.04 (0.91-1.19)

MI 468 (3.4) 639 (4.6) 0.73 (0.65-0.82)

Hospitalization for unstable angina 236 (1.7) 239 (1.7) 0.99 (0.82-1.18)

Stroke 207 (1.5) 262 (1.9) 0.79 (0.66-0.95)

Coronary revascularization 759 (5.5) 965 (7.0) 0.78 (0.71-0.86)

Sabatine MS, et al. March 17, 2017, at NEJM.org..

NEUROCOGNITIVE RISK?• Ebbinghaus Study• Statin + placebo vs. Statin + PCSK9-I• Primary Outcome: Spatial Working Memory

Index• Results:

– No difference in Spatial Memory Scores– Low LDL did not increase risk:– ( LDL <25 mg/dL (0.65 mmol/L))

• Conclusion: Statin + PCSK9-I therapy does not result in neurocognitive adverse effects

Ebbinghaus website: timi.org. Accessed March 20, 2017

NON-STATIN THERAPY PERSPECTIVES

Non-statin therapies may be considered in certain high-risk patients: • Suboptimal response to statin monotherapy• Unable to tolerate the recommended statin dose• Completely statin intolerant


If non-HDL-C and LDL-C goals are not achieved with statin, addition of non-statin therapy should be considered

No data to support combination lipid therapy proving greater ASCVD risk reduction than statin monotherapy


Emphasize adherence to lifestyle and statin before adding non-statin therapy

Fibrates in patients with atherogenic dyslipidemia

Canadian CVD Society:1º: Statin; 2º: Ezetimibe; 3º: BAS; 4º: PSCK9 inhibitors*; Fibrates in ↑ TG/↓ HDL

Elevator Speech: Lipid Management• Determine Non-HDL goal• Use moderate or high intensity statins first• Use fibrates first if TG >500 mg/dL• Do not add fibrates or niacin if already at Non-HDL goal• Use statin combination therapy to achieve

Non-HDL goal depending on lipid profile:• TG >250 mg/dL – fibrates, fish oil, or niacin• LDL >goal – ezetimibe, bile acid resin, niacin, or PCSK9

HYPERTENSION

Pick a goal! Any goal!

Adapted from Blood Pressure: Make Control Your Goal Infographic. CDC.gov. Accessed 1/14/2016.

20 m

mH

g S

BP

or

10

mm

Hg D

BP

CVD risk

doubles

IMPORTANCE OF HYPERTENSION

CONTRIBUTING FACTORS IN THE ELDERLY

Hypertension

Decreased arterial compliance

Endothelial dysfunction

Increased salt sensitivity

Decline in renal function

Left ventricular hypertrophy

Activation of Sympathetic

Nervous System

Decreased Cardiac Output

PATIENT CASE: POLL #3 • A 72 yo Caucasian female presents for

follow-up. Two years ago she had a STEMI and a 3-vessel CABG. PMH also includes HTN, hyperlipidemia, GERD, and depression.

• She is a widow and lives alone, but volunteers at her local church and performs water aerobics at the YMCA 2-3 times a week.

• Current Medications– Quinapril/HCTZ 20/12.5mg daily– Carvedilol 12.5mg twice daily– Esomeprazole 40mg daily– Atorvastatin 80mg daily– Aspirin 81mg daily– Sertraline 50mg daily

• No new complaints and reports she quit smoking after her MI.

• Today’s Vitals– BP 146/84 (RA), 150/88 (LA)– HR 62 (RRR), BMI 30 kg/m2

• Recent labs from 2 months ago– K+ 4.1– SCr 1.1– LDL-C 62 – HbA1c 5.8%

Which of the following would be the most appropriate blood pressure goal for this patient?A. <130/80 mmHgB. <140/80 mmHgC. <140/90 mmHgD. <150/90 mmHg

Lancet. 2002; 360;1903-1913.

VASCULAR MORTALITY AND BLOOD PRESSURE THE “J-CURVE” REVISITED…

JACC 2011:57(20);2037-114.

Adapted From: Denardo SJ, et al. Am J Med 2010; 123(8):719-726

RECOMMENDED BP GOALS IN OLDER ADULTSGuideline

Characteristics (age, comorbidities)

BP Goal (mmHg)

Level of Evidence

JNC 82014

> 60 and without DM or CKD> 60 and with DM or CKD

<150/90<140/90

Strong recommendation – Grade A*Expert Opinion – Grade E*

ASH/ISH2014

> 80 55 – 79

<150/90<140/90

N/A

ACC/AHA2015

>80 with CAD65-79 with CAD

<150/90<140/90

IIa/BExpert Opinion

CHEP 2016

≥ 80 CKDDM

≥50 “High risk”

<150/90<140<130/80<120

Grade CGrade C/AGrade C/A

N/A

ACP/AAFP 2017

≥ 60Stroke/TIA

“Cardiovascular risk”

<150/90<140/90<140/90

Strong recommendation, high qualityWeak recommendation, mod qualityWeak recommendation, low quality

JNC8. JAMA. 2014; 311(5):507-520.ASH/ISH. J Clin Hypertens. 2014; 16(1):14-26.ACC/AHA. JACC. 2015; 65(18):1998-2038.ACP/AAFP.Ann Intern Med. 2017;166(6):430-437

*CAVEATS:• If safe and tolerated, <140 continued• No agreement: low evidence that SBP <140 provides no benefit

IS LOWER THAN 150/90 MMHG BETTER?

• SHEP-Patients ≥ 60 years ISH

Active Treatment

Placebo35 % relative risk reduction in fatal and non-fatal stroke

Average BP Tx:143/68 mm Hg vs. Placebo: 155/72 mm Hg

19% relative risk reduction in cardiovascular disease related deaths

Adapted from JAMA.1995. 265; 24:3255-3264

6.5

10.7

5.3

23.8

0

5

10

15

20

25

Death From Stroke Heart Failure

HYVET (Age>80)

P<0.05

P<0.001

Average BP Tx:144/76 mm Hg vs. Placebo:156/84 mm Hg

Mean Age: 83.6

Tx: indapamide• Perindopril PRN

Follow up: 1.8 years

N Engl J Med.2008. 358;18: 1887-1898

WHAT ABOUT PATIENTS OLDER THAN 60? WHAT ABOUT CAD?• INVEST:

– Hypertensive patients with CAD at least 50 years of age– Randomized to verapamil/trandolapril vs. atenolol/HCTZ to SBP goal of

<140 or <130

• Post-Hoc: – Patients >60 yo with CAD and baseline SBP >150 randomized to three

groups according to SBP at study end: SBP <140 vs. 140-150 vs. >150– Primary Outcome

• all-cause mortality, non-fatal MI, non-fatal stroke

Bangalore S, et al. JACC. 2014; 68(8):784-793.Pepine CJ, et al. JAMA. 2003;290(21):2805-16.

POST-HOC ANALYSIS OF INVESTBaseline Characteristics

Characteristic Mean, all groups (n=8,354)

Age (yrs) 70.7

Age >70 yrs (%) 48.3

Body Mass Index (kg/m2) 28.4

SBP (mmHg) 165.4

DBP (mmHg) 90.2

Diabetes (%) 29

Myocardial infarction (%) 33.9

CABG or PCI (%) 26.6

Angina pectoris (%) 67.2

Unstable angina (%) 11.6

Bangalore S, et al. JACC. 2014; 68(8):784-793. Bangalore S, et al. JACC. 2014; 68(8):784-793.

POST-HOC ANALYSIS OF INVEST

PATIENT CASE: RE-POLL #3 • A 72 yo Caucasian female presents for

follow-up. Two years ago she had a STEMI and a 3-vessel CABG. PMH also includes HTN, hyperlipidemia, GERD, and depression.

• She is a widow and lives alone, but volunteers at her local church and performs water aerobics at the YMCA 2-3 times a week.

• Current Medications– Quinapril/HCTZ 20/12.5mg daily– Carvedilol 12.5mg twice daily– Esomeprazole 40mg daily– Atorvastatin 80mg daily– Aspirin 81mg daily– Sertraline 50mg daily

• No new complaints and reports she quit smoking after her MI.

• Today’s Vitals– BP 146/84 (RA), 150/88 (LA)– HR 62 (RRR), BMI 30 kg/m2

• Recent labs from 2 months ago– K+ 4.1– SCr 1.1– LDL-C 62 – HbA1c 5.8%

Which of the following would be the most appropriate blood pressure goal for this patient?A. <130/80 mmHgB. <140/80 mmHgC. <140/90 mmHgD. <150/90 mmHg

SPRINT: INTENSIVE VS. STANDARD BP

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P=0.001P=0.009

Williamson J, et al. JAMA. 2016;315(24):2673-2682

Baseline Characteristics

Variable Intensive (n=1317)SBP <120

Standard(n=1319)SBP <140

Age (SD) 79.8 (3.9) 79.9 (4.1)

Female Sex 499 (37.9%) 501 (38%)

Systolic BP 141.6 mmHg 141.6 mmHg

Diastolic BP 71.5 mmHg 70.9 mmHg

Framingham Risk 24.2% 25%

Frail Patients 440 (33.4%) 375 (28.4%)

Achieved Blood Pressures

Systolic BP 123.4 62

Diastolic BP 134.8 67.2

Patients 50+ high CVD risk without diabetes

GUIDANCE IMPLICATIONS? CHEP 2016Patients > 50 years WITH:

• Clinical or subclinical cardiovascular disease

• Non-diabetic nephropathy

– GFR 20-59mL/min/1.73 m3

• FRS > 15%

• 75 years + 1 of the above indications

WITHOUT

• HrEF (EF <35%) or M.I. in previous 3 months

• GFR<20 mL/min/1.73 m3

• Diabetes

• Stroke/TIA

• Standing BP <110 mmHg

• Non-adherence

Leung A. et al. Canadian Journal of Cardiology 32 (2016) 569e588

OLDEST OLD: OBSERVATIONAL DATA

• Blood pressure and survival in the oldest old

– U-shape – “Upper limit” of control = best survival

• Blood pressure trends and mortality: the Leiden 85-plus Study

– Blood-pressure trends (↑/↓ average) from age 85-90 and association with mortality to 95

– ↓ SBP associated with ↑ mortality HR 1.45 (1.02-2.06)

– Strongest in institutionalized

Oates DJ< et al. JAGS 2007. 55(3): 383-8Poortvliet RK, et al. J Hypertens. 2013. 31(1):63-70

INSTITUTIONALIZED OLDEST OLD: PARTAGE

Two-fold increased

risk of mortality

JAMA Intern Med. 2015; 175(6):989-995.

DOSE TITRATION OR ADD-ON THERAPY?

Adapted from Wald DS et al.Am J Med. 2009;122:290-300.

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CONSIDERATIONS IN THE OLDER ADULT

• Fewer robust individuals by age– Common in very old, robust

individuals & treatment beneficial

• 60-79 years without compelling indications: BP<140/90mmHg if tolerated

• SPRINT implications for high risk recommendations?

• More susceptible to orthostatic hypotension and polypharmacy

• Preferred 1st line agents:– Thiazide diuretics– ACE-I or ARB– Calcium Channel Blocker

• Start low, go slow

• Consider 2 drugs, at low doses, if >20/10 mmHg from BP goal

JACC. 2011; 57:2037-114.

Measure the blood pressure accurately, frequently, and at different times of the day!

STROKE PROPHYLAXIS IN PATIENTS WITH ATRIAL FIBRILLATION (AF)

ISCHEMIC STROKE AND AF• AF increases the risk of

stroke 5-fold

• Age and multi-morbidity may increase risk

• Stroke due to AF is associated with a greater risk of recurrent stroke, disability, and mortality

JACC. 2014; 64(21):2246-2280.

ROLE OF THE LEFT ATRIAL APPENDAGE (LAA)

• Decompression chamber during systole and when atrial pressure is high

• 90% of AF-related strokes originate in the LAA

• LAA closure (WATCHMAN device)– FDA approved in March 2015

– Reasonable when chronic anticoagulation is undesirable.

– 99% off warfarin within one year

JACC. 2014; 64(21):2246-2280.

CHADS2 VERSUS CHA2DS2-VASC

CHADS2 Score

Heart Failure 1

Hypertension 1

Age >75 years old 1

Diabetes 1

Prior Stroke/TIA 2

Maximum Score = 6

CHA2DS2-VASc Score

Heart Failure 1

Hypertension 1

Age >75 years old 2

Diabetes 1

Prior Stroke/TIA 2

Vascular Disease (e.g., MI, PAD, aortic plaque)

1

Age 65 – 74 years old 1

Female gender 1

Maximum Score = 9

Key Differences…1. Age >75 years old is given greater

consideration (i.e., 2 points instead of 1 point).

2. CHA2DS2-VASc includes additional risk factors not included in CHADS2.

JACC. 2014; 64(21):2246-2280.

CHA2DS2-VASC

CHA2DS2-VASc Score Stroke Prophylaxis Recommendation

0It is reasonable not to give antithrombotic therapy

1

Any of the following are reasonable:• Omit antithrombotic therapy• Oral anticoagulation• Antiplatelet therapy*

>2 Oral anticoagulation is warranted

*Aspirin therapy has been shown to be ineffective in preventing strokesin patients >75 years of age.

JACC. 2014; 64(21):2246-2280.

ORAL ANTICOAGULATION EVOLUTION

1954

WarfarinCoumadin®

2010 Dabigatran Pradaxa®

2011 Rivaroxaban Xarelto®

2012

Apixaban Eliquis®

2015 Edoxaban

Sivaysa®

In 2006, the development of the first oral direct thrombin inhibitor, ximelagatran, was was halted due to hepatotoxicity.

FDA Approval

Intrinsic Pathway (Contact Activation)

Extrinsic Pathway (Tissue Factor)

VIII VII

X

V

II

XII XI IX

Fibrinogen Fibrin Clot

Warfarin

Factor Xa Inhibitors • Apixaban• Edoxaban• Rivaroxaban

Direct Thrombin Inhibitor• Dabigatran

EDOXABAN (SAVAYSA) • Edoxaban is a Factor Xa inhibitor approved to reduce stroke risk in

patients with nonvalvular AF and for the treatment of DVT/PE and DVT following 5-10 days of a parenteral anticoagulant.

• Pharmacokinetics– The bioavailability is not affected by food.– Reaches Cmax in 1-2 hrs and has an elimination half-life of 10-14 hrs. – Primarily eliminated in the urine (50% of total clearance).– Minimally metabolized by CYP3A4.

Edoxaban [SavaysaTM]. Package Insert.

Characteristic Non-Valvular AF Dosing

CrCl >95mL/min *DO NOT USE

CrCl 51-95 mL/min 60mg once daily

CrCl 15-50 mL/min 30mg once daily

Notes from ENGAGE-TIMI 48 trial in patients with non-valvular AF: Patients had their doses halved (60mg to 30mg, or 30mg to 15mg) if one or more of

the following were present: body weight <60 kg, concomitant use of verapamil, quinidine, or dronedarone.

An increased risk of stroke was observed in a subgroup of patients with CrCl >95 mL/min.

EDOXABAN (SAVAYSA): DOSING

Characteristic DVT/PE Treatment Dosing

CrCl >50 mL/min 60mg once daily

CrCl 15-50 mL/min ORBody weight <60 kg

30mg once daily

Edoxaban [SavaysaTM]. Package Insert.

EDOXABAN (SAVAYSA)Advantages

• Non-inferior to warfarin in preventing stroke and associated with less major bleeding

• Once-daily administration• No monitoring required• Few significant drug-drug

interactions• No significant non-bleeding

adverse events• May be crushed

Disadvantages

• Contraindicated in patients with CrCl >95 mL/min

• Place in therapy? No distinct advantage over other recently approved agents

• Reversal agents are currently under investigation

EMERGING REVERSAL AGENTS

• Andexant – Developed by Portola Pharmaceuticals, Inc.– Recombinant molecule that is a direct reversal agent for factor-Xa inhibitors– Single IV bolus– February 2015 Received orphan drug status from the FDA

• Idarucizumab – Developed by Boehringer Ingelheim– Humanized antibody fragment that binds directly to dabigatran– Two bolus infusions given <15 minutes apart– March 2015 Received orphan drug status from the FDA

• Aripazine – Developed by PerosphereTM– Synthetic small molecule effective against ALL anticoagulants (except warfarin)– Single IV bolus

Pollack CV, et al. NEJM. 2015(June 22).[Epub ahead of print].Ansell JE, et al. NEJM. 2015; 371(22): 2141-2142.Lu G, et al. Nat Med. 2013; 19(4):446-451.

PATIENT CASE: POLL #4• A 75 yo male is scheduled for

colonoscopy next month• PCP questions periprocedural

management of warfarin• PMH includes atrial fibrillation,

HTN, arthritis, GERD• CHADS2 and CHA2DS2-VASc

Scores = 3• Normal renal/hepatic function

• Medications:– Warfarin (target INR 2-3)– Lisinopril 10mg daily– Amlodipine 10mg daily– Omeprazole 20mg daily– Acetaminophen 650mg twice

daily

Which of the following would be the most appropriate periprocedural option for this patient?A. Continue warfarin throughout procedureB. Hold warfarin x 5 days without a LMWH bridgeC. Hold warfarin x 5 days and bridge with LMWHD. Discontinue warfarin and change to dabigatran

“TO BRIDGE OR NOT TO BRIDGE?”• Hypothesis:

– No bridging would be noninferior to bridging for prevention of perioperative arterial thromboembolism in patients with atrial fibrillation and would be superior to bridging with respect to major bleeding.

• Design: Randomized, double-blind, placebo-controlled study– 100 IU dalteparin per kg of body weight or matching placebo

– Warfarin stopped 5 days before the procedure and resumed within 24 hours

– Excluded patients with recent stroke/bleed, CrCl <30, PLT <100

– 30-day follow up period

• Primary outcome: arterial thromboembolism and major bleeding

N Engl J Med. 2015; June 22: [Epub ahead of print].

BRIDGE: POPULATION CHARACTERISTICS

• Enrolled 1,884 patients – Mean age: 72 years– Male (73%)– Caucasian (90%)– Mean CHADS2 = 2.3– 18% with prior history of stroke or TIA– 35% on aspirin therapy and 2.5% on clopidogrel– Wide range of surgeries and procedures

• Most common were GI, orthopedic, urologic, cardiothoracic


BRIDGE STUDY: RESULTS


SAFETY OF TSOACS IN THE ELDERLY

• Concerns with use of TSOACs in those >75 yo– Dabigatran was penalized for being the first horse out of the gate…– Reports of major bleeding with dabigatran were often in patients >80 years of age and nearly

60% had moderate-severe renal impairment – Mean age of the RE-LY trial participants 71 – Those >75 years of age underrepresented

• A meta-analysis evaluated the safety of dabigatran, apixaban, and rivaroxaban in elderly adults and found no excess risk of major bleeding in those >75 years of age.

• Nevertheless, exercise caution with TSOACS in the older adult. • An individualized approach is warranted as there appears to be no single agent

that can be generalized for use in all patients.

Drugs Aging. 2013;30(8):593-601.J Am Geriatr Soc. 2014;62:857-864.

TSOACS: target-specific oral anticoagulants

ANTIPLATELET THERAPY AFTER ACS

DUAL ANTIPLATELET THERAPY DURATION

• Extended duration beyond 1 year: meta analysis– n = 21,534 patients from 3 studies– Aspirin + ticagrelor/clopidogrel/prasugrel– NNT 64/2.5 years to reduce composite of CV death, MI or stroke– NNT 220/2.5 years for cardiovascular mortality– No efficacy difference by platelet inhibitor– Not associated with significant increase in major bleeding (OR

1.53, 0.72-0.97 p = 0.10)• More likely with ticagrelor or prasugrel versus clopidogrel

CHRONIC HEART FAILURE

NEW THERAPIES

ENTRESTO (SACUBITRIL/VALSARTAN)

• Indication: to reduce the risk of CV death and hospitalization for HF patients (NYHA Class II-IV) with a reduced EF in place of an ACE inhibitor or ARB

• MOA: neprilysin inhibitor (sacubitril) and valsartan; increase natriuretic peptides degraded by neprilysin

• Dose: 49/51mg PO BID x 2-4 weeks, then titrate up to 97/103mg BID (if tolerated) – also available in a lower dose, 24/26mg

• SE: hypotension, hyperkalemia, cough, dizziness, renal failure

Sacubitril/Valsartan [EntrestoTM]. Package Insert.

CORLANOR (LANCORA) (IVABRADINE)• Indication: to reduce the risk of hospitalization for worsening HF in stable,

symptomatic HF with a reduced EF, in sinus rhythm, resting HR >70 (77 in Canada); on maximally tolerated doses of beta-blockers/contraindication to a beta-blocker

• MOA: selectively blocks the HCN (“funny”) channel responsible for the cardiac pacemaker If current, which slows diastolic depolarization and decreases heart rate

• Dose: 5mg PO BID x 2 weeks, then titrate up to 7.5mg BID (if tolerated)

• SE: bradycardia, increase BP, atrial fibrillation, luminous phenomena

• Avoid with strong CYP3A4 inhibitors

Ivabradine [Corolanor®]. Package Insert.

RECOMMENDED TOOLS

• American College of Cardiology Clinical Apps

– http://www.acc.org/tools-and-practice-support/mobile-resources?w_nav=MN

http://www.acc.org/tools-and-practice-support/mobile-resources?w_nav=MN

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