·:{iC0Fp'16ACOFP 53rd Annual Convention & Scientific Seminars

Management of Hypertension and Dyslipidemia in 2016

Daniel Tarditi, DO

3/17/2016

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Management of Hypertension

and Dyslipidemia in 2016Daniel 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?

HypertensionA 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

Oral contraceptives

(estrogen predominatnt)

Sympathomimetic agents

(decondestants, diet pills,

etc)

Stimulants (amphetamines,

methylphenidate)

Alcohol

Antidepressants (TCAs and

SNRIs)

Cyclosporine

Erythropoietin

Natural licorice

Herbal compounds

(ephedra or ma huang)

Should we treat hypertension in the

elderly?Systolic Hypertension in the Elderly Program (SHEP)

JAMA. 1991;265:3255-3264.

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)

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

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

Blood Pressure Separation1st 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 8No Diabetes or CKD

JNC 8Diabetes 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

SPRINTSystolic BP in two treatment groups during course of the trial

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

SPRINTPrimary Outcome and CV Death

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

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SPRINTForest 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

SPRINTSummary

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 SPRINTTale of Two Trials?

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

HypertensionWhat 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 hyperinsulinemicmicroalbuminuria

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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Insulin Resistance, Metabolic Variables, and CAD

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

National Health And Nutrition Examination Survey (NHANES) 1998-2004

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.

Lab Analysis of ApoB Lipoproteins

VLDL-C

LDL-C

ApoB Lipoproteins

Chylomicrons

VLDL-P

IDL-P LDL-P

VLDLs IDLs LDLs

ApoB Concentration

TG/5 TC – HDL-C + VLDL-C

January 5,1967 Volume 276

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April 2008

Diabetes Care 2008;31:811-822

JACC 2008;51:1512–24

41 Years after the

NEJM article

Suggested Treatment Goals in Patients with

CMR and Lipoprotein Abnormalities

Goals

LDL cholesterol

(mg/dL)

Non-HDL cholesterol

(mg/dL)

ApoB

(mg/dL)

1) Known CVD or

2) DM plus one or more additional major CVD risk factor<70 <100 <80

1) No DM or known clinical CVD but two or more

additional major CVD risk factors or

2) DM but not other major CVD risk factors

<100 <130 <90

Other major risk factors (beyond dyslipoproteinemia) include:

•Smoking

•Hypertension

•Family history of premature CAD

Relationship of Triglycerides

and LDL Particle Size

Cu

mu

lati

ve %

Fre

qu

ency

Austin M, et al. Circulation. 1990;82:495-506.

0102030405060708090

100

0 40 80 120 160 200 240 280

Triglyceride mg/dL

Small, Dense LDL (pattern B)

Large, Buoyant LDL (pattern A)

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Lipoprotein Abnormalities in

Hypertriglyceridemic States

TG-rich VLDL

(CETP)

Large LDL

Large

HDL

TG

(CETP)

TG

CE

CE

TG-enriched

Cholesterol-depleted

particles

Triglyceride Cholesteryl ester

CETP exchange of CE for

TG results in less cholesterol

per LDL & HDL particle than

previously

LDL-C & HDL-C

VLDL-C

apoB

apoCII

apoE

Apo A-V

LDL Particle Abnormalities in

Hypertriglyceridemic States

TG-rich VLDL

(CETP)

Large TG-rich LDL

Large

HDL

TG

Small LDL

Hepatic

Lipase(CETP)

TG

CE

CE

TG-enriched

Cholesterol-depleted

particlesLipoprotein Lipase

Smaller

cholesterol-rich

VLDL remnants ~ LDL-C

Triglyceride Cholesteryl ester

Total LDL-PSmall LDL-P LDL size

HDL Particle Abnormalities in

Hypertriglyceridemic States

TG-rich VLDL

(CETP)

Large TG-rich LDL

Smaller HDLLarge TG-rich

HDL

TG

Small LDL

Hepatic

Lipase

Hepatic

Lipase

(CETP)

TG

CE

CE

Lipoprotein Lipase

Smaller

cholesterol-rich

VLDL remnants

HDL-C

Total HDL-P

HDL size

Large LDL-P

ApoA-I

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LDL Cholesterol and LDL Particle Numbers in T2DM

Patients with LDL-C < 100 mg/dL (n=2,355)

0

5

10

15

20

700 1000 1300 1600 (nmol/L)

31%

(n=741)

38%

(n=891)

16%

(n=383)

8%

(n=178)

Percent

of

Subjects

7%

(n=162)

LDL-P

0

10

20

30

70 100 130 160 (mg/dL)

63%

(n=1485)

Percent

of

Subjects

37%

(n=870)

5th 20th 50th 80th percentile

LDL-C

62%

AHA Scientific Sessions, 2005

Population Distributions of LDL-P in Framingham

Offspring Study and the Multi-Ethnic Study of

Atherosclerosis (MESA)Percentile LDL-C

(mg/dL)

LDL-C

(mg/dL)

LDL-P (nmol/L)

LDL-P

(nmol/L)

2 70 720

5 78 70 850 770

10 88 81 940 940

20 100 93 1100 1000

30 111 103 1220 1070

40 120 110 1330 1100

50 130 118 1440 1190

60 139 125 1540 1280

70 149 133 1670 1480

80 160 143 1820 1610

90 176 160 2020 1790

95 191 171 2210 1980

50th Percentile Cutpoint

20th Percentile Cutpoint

2nd Percentile Cutpoint

5th Percentile Cutpoint

MESA in red font

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-ITpresented 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 TrialsAll 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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danieltarditi@verizon.net

Cell phone: 609-238-9572