·:{iC0Fp'16

ACOFP 53rd Annual Convention & Scientific Seminars

Management of Hypertension
and Dyslipidemia in 2016

Daniel Tarditi, DO
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Management of Hypertension
and Dyslipidemia in 2016
Daniel Tarditi, DO FACC
The Heart House, Cardiovascular Associates of the Delaware Valley

Game Plan
Hypertension
 Brief overview of trials that led us to where we are
today
 Why the new goals in JNC-8?
 What has changed our management since JNC-8 was
released?
Dyslipidemia
 How do you incorporate new guidelines into current
practice?
 What’s new and on the horizon?

Hypertension
A Major Public Health Crisis

 Contributes to >360,000 deaths every year in the US

 Poor medication adherence is a major barrier to
effective BP management
 Only about 57% of patients remain adherent to their
medications

 The prevalence of hypertension in the US is about 29.1%

among adults, nearly 1 in 3 Americans
 2011 NHANES data
 83% of individuals aware they have high BP
 Control rate is about 53%

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Drug-Induced (Medications) that

Can Interfere with BP Control
 NSAIDs/COX-2 Inhibitors  Antidepressants (TCAs and
SNRIs)
 Oral contraceptives
(estrogen predominatnt)  Cyclosporine

 Sympathomimetic agents  Erythropoietin

(decondestants, diet pills,
etc)  Natural licorice

 Stimulants (amphetamines,  Herbal compounds

methylphenidate) (ephedra or ma huang)

 Alcohol

Should we treat hypertension in the

elderly?
Systolic Hypertension in the Elderly Program (SHEP)
Multicenter, randomized, double-blind, placebo-controlled, >60 yrs old, systolic BP ≥ 160
mmHg & diastolic BP <90 mmHg, using 12.5-25 mg chlorthalidone + other drugs PRN
(Starting SBP: 170 mmHg; achieved SBP: Placebo 155, active treatment 143)

JAMA. 1991;265:3255-3264.

Systolic Hypertension in Europe

Trial (Syst-Eur)
Randomized, double-bind placebo trial of pts >60 with isolated systolic HTN.
Goal: Lower SBP by 20 mmHg to <150: placebo = 161mmHg; active = 151 mmHg

Placebo vs Nitrendipine 10-40 ± enalapril 5-20 mg ± HCTZ

Lancet. 1997;350:757-764.

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How Many Drugs Do Most Patients Need

to Achieve Goal Blood Pressure?

Am J Kidney Disease. 2000;36(3): 646-661.

Major Outcomes by Achieved SBP

Category in the ACCOMPLISH Trial

* CV death or non-fatal MI or non-fatal stroke Amer J Med 2013; 126:501-508.

Blood Pressure Separation

1st trial to show benefit in very elderly (≥80 years old)

NEJM. 2008; 358: 1887.

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Total Mortality
(21% Reduction)

NEJM. 2008; 358: 1887.

ACCORD: Systolic Pressures (mean ± 95% CI)

Compared <140 mmHg vs < 120 mmHg
DM AND >40 years old with CVD OR >50 with 2+ CVD risk factors

NEJM. 2010;362: 1575-1585.

ACCORD: Results

NEJM. 2010;362: 1575-1585.

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Initial Conclusions
 Best cardiovascular protection associated for most
people with target systolic BP <140 mmHg

 Over age 80, SBP <150 mmHg is established

 Stroke: After age 60 it becomes the most common

outcome of hypertension

 Based on SHEP and ACCORD, every 1 mmHg by which

SBP is lower provides a relative 2-3% reduction in stroke
rates

ALLHAT
Study Design

JAMA. 2002:288:2981-2997.

Chlorthalidone 25 mg has greater BP Lowering

Efficacy than HCTZ 50 mg, but what is a Fair
Dose Comparison?

Hypertension. 2006;47:352-358.

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JNC 8 Panel Guidelines:

Initial Choices of Medications

JAMA. 2014;311:507-520.

JNC 8
No Diabetes or CKD

JNC 8
Diabetes or CKD

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Why was there discord among

minority of JNC 8 Panel?
 Target SBP of 150 mm Hg for ≥60 without diabetes or
CKD
 Evidence to support increase of target from 140 to
150 was insufficient and inconsistent with
evidence (SHEP and HYVET)
 Higher SBP goal may increase stroke mortality
 Other guidelines recommend SBP <140, especially
for age <80
 ESH/ESC
 ASH/ISH

Why was there discord among

minority of JNC 8 Panel?
 On the basis of absolute risk, using an age
threshold of 60 years to define eligibility for
less aggressive treatment lacks consistency.
Persons aged 60 to 79 years are at higher
risk than those who are younger, even if the
younger persons have DM

Insufficient Evidence for Differential

Treatment Benefit for Age >60 or <60
 No qualifying evidence comparing SBP <140 to other SBP
for age < 60

 Evidence for treating SBP to <140 for age >60

1. SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264.

2. HVET Study Group. NEJM. 2008;358:1887-1898.

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 N = 9361. No diabetes or prior stroke. 31% women enrolled

 Study requirements:
 ≥50 years old, SBP 130-180 mm Hg,AND:
  risk of CV events (clinical or subclinical CV disease other than
stroke); CKD; 10 yr FRS of 15% or greater OR ≥75 years old

 Tested whether a treatment strategy aimed at reducing SBP to

 Lower goal (SBP <120 mm Hg) compared with currently
recommended (SBP < 140 mm Hg)

 Primary outcome – composite of

 MI, Stroke, CHF, ACS other than MI, CV death

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

SPRINT
Systolic BP in two treatment groups during course of the trial

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

SPRINT
Primary Outcome and CV Death

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

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SPRINT
Forest Plot of Subgroups

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

SPRINT Results
 50% were unable to achieve a target BP <120 mm Hg

 Number of medications required to achieve targets: 3 vs 2

 Side effects
 Hypotension (2.4% vs 1.4% p = 0.001)
 Syncope (2.3 vs 1.7) p = 0.05
 Electrolyte abnormalities (3.1 vs 2.3) p = 0.02
 Kidney injury or failure (4.1 vs 2.5) p < 0.001
 Orthostasis (16.6 vs 18.3) p = 0.001

The SPRINT Research Group. N Engl J Med 2015;373:2103-2116

SPRINT
Summary

Among patients at high risk for cardiovascular

events but without diabetes, targeting a systolic
blood pressure of <120 mm Hg, as compared
with <140 mm Hg, resulted in lower rates of
fatal and nonfatal major cardiovascular events
and death from any cause.

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ACCORD versus SPRINT

Tale of Two Trials?

Perkovic V, Rodgers A. N Engl J Med 2015;373:2175-2178.

Hypertension
What to do in practice?
For those with increased risk of
cardiovascular events/disease
 Initiate therapy at SBP 140 and aim for target of
<130 with goal closer to 120 mm Hg as tolerated
 If treating aggressively, need close follow-up and
management
 Opinion: JNC 8 and BP goals should be amended
 Reasonable to use new SBP of 150 for frail
patients over the age of 80

Cholesterol Management in 2016

 What’s new in the 2013 ACC/AHA Cholesterol
Guidelines

 NLA Guidelines

 Consensus for our future population

 What’s new on the horizon

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The NHLBI Charge to Expert

Panel

Overview of changes
 No specific target for LDL-c or non-HDL-c
 Identified 4 groups to benefit from statins

 New risk calculator for 10 year and 30 year (lifetime) risk

 Tried to be purely “evidence based”

Why no target for treatment?

 Do not recommend for OR against a specific LDL-c or
non-HDL-c target for primary or secondary prevention

 Recommend AGAINST specific targets as performance

measures

 Uncertain value of albuminuria, renal insufficiency,

ApoB, LDL-p, and cardiovascular fitness level

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Albuminuria
 Circulation 2002;106(14);1777. (N=85,421)
 Urinary albumin excretion is a predictor of all-cause mortality
in general population. Excess risk was more attributable to
death from CV causes, independent of other CV risk factors.
 30% increased risk of CV mortality

 Circulation 2001;103(25):3057 (N=12,239)

 4x increased risk for cardiovascular mortality with highest
quartile of albuminuria

 Circulation 1995;91(3):831 (N=1069)

 Odds ratio of 7.9 for CHD death with hyperinsulinemic
microalbuminuria

Renal Function and Risk

 Even earliest stages of CKD
associated with higher risk of
subsequent coronary heart
disease

 Assessment of CKD in addition

to conventional risk factors
modestly improves prediction of
risk for CHD

 Provides about half as much

predictive gain as does history
of DM or about 1/6 as much as
does a history of smoking

BMJ 2010;341;c4986

Lipids, Lipoproteins and Apolipoproteins

in the INTERHEART Study

Lancet 2008;372:224-233.

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Overview of changes
 No specific target for LDL-c or non-HDL-c

 Identified 4 groups to benefit from statins

 New risk calculator for 10 year and 30 year (lifetime)
risk

 Tried to be purely “evidence based”

Four Statin Benefit Groups

Intensity of Statin Therapy

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

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Why the LDL-c ≥ 190 mg/dL

category
Recognition of FH and Its Treatment in a National
Survey 2014-2015 (n= 390)

• 30 year old male with LDL-c 210 mg/dL.

What would you recommend?

Overview of changes
 No specific target for LDL-c or non-HDL-c

 Identified 4 groups to benefit from statins

 New risk calculator for 10 year and 30

year (lifetime) risk
 Tried to be purely “evidence based”

New risk calculator

 Recommended every 4-6 years to calculate
traditional risk factors in patients without ASCVD
20-79 years of age
 Probably OVERestimates risk
 Now calculates risk of CHD AND stroke for ten
years as well as 30 years (lifetime risk)

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Ridker et al. Lancet analysis

New ACC/AHA Risk Calculator

What about my patient not in any

of groups and risk < 7.5%?
 Can use:
 hsCRP ≥ 2 mg/dL
 Family history of ASCVD
 LDL-c ≥ 160 mg/dL
 Coronary calcium score ≥ 300 Agatston units or ≥
75th percentile for age
 Ankle-brachial index < 0.9

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Guidelines versus consensus

recommendations

Why the increased incidence of

insulin resistance?

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National Health And Nutrition

Examination Survey (NHANES) 1998-2004
Insulin Resistance, Metabolic Variables, and CAD

Of the risk factors that are sufficiently well studied to

permit quantitative analysis, insulin resistance is the
most important single risk factor for CAD. Our results
indicate that insulin resistance is responsible for
approximately 42% of myocardial infarctions.
Its effect on CAD is indirect, mediated through its
effects on other variables such as SBP, HDL-cholesterol,
triglycerides, glucose, and apolipoprotein B.

Eddy D et al. Diabetes Care 32:361–366, 2009

Lab Analysis of ApoB Lipoproteins

ApoB Concentration

VLDL-P
IDL-P LDL-P
Chylomicrons
VLDLs IDLs LDLs

LDL-C
VLDL-C TG/5 TC – HDL-C + VLDL-C

ApoB Lipoproteins

January 5,1967 Volume 276

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April 2008

41 Years after the

NEJM article

Diabetes Care 2008;31:811-822

JACC 2008;51:1512–24

Suggested Treatment Goals in Patients with

CMR and Lipoprotein Abnormalities
Goals
LDL cholesterol Non-HDL cholesterol ApoB
(mg/dL) (mg/dL) (mg/dL)

1) Known CVD or
<70 <100 <80
2) DM plus one or more additional major CVD risk factor
1) No DM or known clinical CVD but two or more
additional major CVD risk factors or <100 <130 <90
2) DM but not other major CVD risk factors

Other major risk factors (beyond dyslipoproteinemia) include:

•Smoking
•Hypertension
•Family history of premature CAD

Relationship of Triglycerides
and LDL Particle Size
Large, Buoyant Small, Dense
100 LDL (pattern A) LDL (pattern B)
90
Cumulative % Frequency

80
70
60
50
40
30
20
10
0
0 40 80 120 160 200 240 280

Triglyceride mg/dL
Austin M, et al. Circulation. 1990;82:495-506.

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Lipoprotein Abnormalities in
Hypertriglyceridemic States
TG-rich VLDL Large LDL
Apo A-V CE CETP exchange of CE for
apoCII
TG results in less cholesterol
(CETP) per LDL & HDL particle than
apoE
previously
TG
TG-enriched
Cholesterol-depleted
apoB CE particles
(CETP)

TG LDL-C & HDL-C

Large VLDL-C
HDL

Triglyceride Cholesteryl ester

LDL Particle Abnormalities in

Hypertriglyceridemic States
TG-rich VLDL Large TG-rich LDL Small LDL
CE
Hepatic
Lipase
(CETP)

Total LDL-P
TG
Small LDL-P LDL size

CE TG-enriched
(CETP) Cholesterol-depleted
Lipoprotein Lipase
particles
Smaller TG
cholesterol-rich
VLDL remnants Large ~ LDL-C
HDL

Triglyceride Cholesteryl ester

HDL Particle Abnormalities in

Hypertriglyceridemic States
TG-rich VLDL Large TG-rich LDL Small LDL
CE
Hepatic
Lipase
(CETP)
HDL-C
TG ApoA-I

CE
(CETP)
Lipoprotein Lipase
Hepatic
Smaller TG Lipase
cholesterol-rich Smaller HDL
VLDL remnants Large TG-rich
HDL HDL size

Large LDL-P Total HDL-P

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LDL Cholesterol and LDL Particle Numbers in T2DM

Patients with LDL-C < 100 mg/dL (n=2,355)
5th 20th 50th 80th percentile
30
37% 63%
(n=870) (n=1485)

20

Percent
of LDL-C
Subjects 10

0
70 100 130 160 (mg/dL)
20
7% 31% 38% 16% 8%
(n=162) (n=741) (n=891) (n=383) (n=178)
15
62%
Percent
10
of
Subjects
LDL-P
5

0
700 1000 1300 1600 (nmol/L)
AHA Scientific Sessions, 2005

Population Distributions of LDL-P in Framingham

Offspring Study and the Multi-Ethnic Study of
Atherosclerosis (MESA)
Percentile LDL-C LDL-C LDL-P LDL-P
(mg/dL) (mg/dL) (nmol/L) (nmol/L)
2 70 720 2nd Percentile Cutpoint

5 78 70 850 770 5th Percentile Cutpoint

10 88 81 940 940
20 100 93 1100 1000 20th Percentile Cutpoint
30 111 103 1220 1070
40 120 110 1330 1100
50 130 118 1440 1190 50th Percentile Cutpoint

60 139 125 1540 1280

70 149 133 1670 1480
80 160 143 1820 1610
90 176 160 2020 1790 MESA in red font
95 191 171 2210 1980 FOS in black

Update Since Guidelines

 What about patients not at goal – if
you use targets
 What is new on the horizon

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IMPROVE-IT
presented at AHA 2014

 Large scale (18,144 participants), multi-center RCT

of high risk post ACS patients

 Intervention: ezetimibe 10 mg added to

simvastatin 40 mg

 Comparator: Simvastatin 40 mg
 Both groups achieved a mean LDL-c < 70 mg/dl

 Study took 9 years; follow-up was 7 years

 No increase in side effects with intervention

New Therapies

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PCSK9 Inhibition
(Proprotein Convertase Sutilisin/Kexin type 9)

Ongoing PCSK9 Inhibitor CVD

Outcome Trials
All performed on background of high intensity or maximally tolerated statin
therapy with >50% further reduction LDL-c

• LAPLACE-2 Evolocumab for 12 wks 1117 pts

• Statin intolerant pts 63-75% LDLc vs 20% with ezetimibe

• RUTHERFORD-2 Evolocumab 12 wks with He FH 331 pts

• 80% Rx had LDL-c <70 mg/dl vs 2% control

• ODYSSEY OUTCOMES
• Alirocumab NCT01663402
• ACS (N = 18,000)

• FOURIER
• Evolocumab NCT01764633
• Very high risk CVD (N = 22,500)

• SPIRE 1 & 2
• Bococizumab NCT01975376 & NCT01975389
• High CVD risk

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Summary of Evolocumab
  LDL-c by 61% at 12 weeks
 Absolute decrease of 73 mg/dL
 Median achieved LDL-c of 48 mg/dL

  CV outcomes by 53% over 1 year

 Pre-specified, exploratory outcome with relatively few events
 Event curves diverged early & continued to separate over time
 Consistent effect on death, coronary and cerebrovasc events
 Consistent effect in major subgroups

 Appeared to be safe and well-tolerated

 Adverse events largely balanced, good tolerability
 No gradient incidence of any AE by achieved LDL-c, including
those with LDL-c <25 mg/dL

What are some common themes

across the guidelines?
ACC/AHA 2013, NLA 2014, CCS 2012, ECS/EAS 2011

1. Aggressive treatment of patients with established

cardiovascular disease (ASCVD), diabetes, and primary
LDL-c ≥190 mg/dL

2. Statins as “first line therapy” for these high-risk

patients

3. Short and long-term CVD Risk Calculation to inform

risk discussion

4. Follow-up testing as either target of therapy or

monitor response/adherence

Summary
 Guidelines are based on evidence from RCTs that are
limited by the trial design
 They are necessarily conservative in providing
population-based recommendation that physicians must
interpret in the context of individual patient care
 I believe the NLA guideline provides comprehensive,
scientific, evidence-based recommendation to assist
clinical judgment for individual patient care
 Serum ApoB is cheap, reproducible, effective method
for better risk stratification than LDL-c or non-HDL-c
alone

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[email protected]
Cell phone: 609-238-9572

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