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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
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+
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
ACC/AHA 2013 NLA 2014
Provider-patient discussion should consider drug-drug interactions, polypharmacy, concomitant medical conditions including frailty, cost considerations, and patient preference.
Stone NJ, et al. Circulation. 2014;129:S1-S45.Jacobson TA et al. J Clin Lipid. 2014;8:473-488.
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
IMPROVE-IT (TIMI 40) website. www.timi.org. Accessed 5/4/2015.
*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 (TIMI 40) website. www.timi.org. Accessed 5/4/2015.
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
IMPROVE-IT (TIMI 40) website. www.timi.org. Accessed 5/4/2015.
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
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
ACC/AHA 2013 NLA 2014
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
Stone NJ, et al. Circulation. 2014;129:S1-S45.Jacobson TA et al. J Clin Lipid. 2014;8:473-488.
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
020406080
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CompositeCVD Disease
Measure
Mortality
Axi
s Ti
tle
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.
1.04 11.16
0.891.01
0.19* 0.23* 0.2*0.37*
0.22*
0
0.5
1
1.5
Thiazide BetaBlocker
ACE-I CCB AllClasses
Adding Drug FromAnother Class (onaverage standard doses)
Incr
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“The additional effect of combining given doses of 2 classes of drug is approximately 5 times more effective than doubling the dose of 1 drug”
60
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
N Engl J Med. 2015; June 22: [Epub ahead of print].
BRIDGE STUDY: RESULTS
N Engl J Med. 2015; June 22: [Epub ahead of print].
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