Update in CardiologyFocus on Prevention

Andrew Teklinski, MD, MS, FACC

Cardiology

Munson Medical Center

Financial Disclosures

• None

CVD: Where are we at?

Carotid atherosclerosis

Carotid atherosclerosis

The Good News (Sort of)

The Good News

The Bad News

• CVD remains the leading cause of death in the US

– 840,768 deaths (635,260 cardiac) in 2016

– From 2006 to 2016, the US death rate from CVD decreased by 18.6% and

from CHD 31.8%

• Annual estimated cost of CVD in the US was $351.2 billion in 2014-2015,

with $213.8 billion in direct cost, including 46% for inpatient care

• About every 40 seconds an American will have an MI

• In the US in 2019, coronary events are expected in 1,055,000 individuals

including 720,000 new and 335,000 recurrent coronary events

Heart Disease and Stroke Statistics-2019 Update: A Report from the American Heart Association. Circulation 2019; Jan 31

The Changes To Our Current Plan• More accurate assessment of risk

– Coronary calcium scores

– Expanded risk assessment tools

• Prevention• Hypertension

• Diabetes

• Lipids

• Medical management

– Fish oil

– Anti inflammatory

– PCSK 9 inhibitors

– Anti coagulants

– ASA

– Antidiabetes meds

– Nonpharmacologic management

• Valvular disease

Lipid management guidelines (changes from 2013)

• 2013: Made use of pooled cohort equations for primary prevention, which provide good 10 year estimates of risk in most situations

– Variables: Race, gender, age, total cholesterol, HDL, Systolic BP, hypertension, diabetes, smoking

• 2018: Update

– Continued use of the pooled cohort equations

– Added concept of risk enhancers

• Family history

• Metabolic syndrome

• Chronic kidney disease

• Chronic inflammatory diseases: psoriasis, rheumatoid arthritis, HIV

• Certain ethnicity (South Asian descent: India, Bangladesh, Sri Lanka, Bhutan and the Madives; 4 fold higher risk than the general population and tend to develop it 10

years earlier)

• History of premature menopause or preecclampsia

• High levels of Lp(a) or apolipoprotein B

• Coronary artery calcium score

– May help as a “tiebreaker” for persons who are candidates for statin therapy in primary prevention, but unsure about committing to a long-term course of

statin therapy

• Added recommendations for ezetimibe (Zetia), evolocumab (Repatha) and alirocumab (Praluent) to secondary prevention patients unable to achieve LDL goals (<70) on statin alone.

• Use of non fasting lipid levels is acceptable in most circumstances

Coronary artery calcium score

• Non contrast CT scan

• Radiation dose of about 1 mSv ~ the same

radiation dose as a mammogram

• Not covered by insurance

• Costs $50-$300 out of pocket

Coronary CT

• Coronary calcium score

• Coronary CT angiogram

Prevention

• Medical management

– SGLT2 inhibitors

– GLP1 agonists

– PCSK9 Inhibitors

– Rivaroxiban

– ASA

– Eicosapent ethyl/omega 3

– Bempedoic acid

Omega 3 Fatty Acids• Bang and Dyerberg in 1970’s reported that Greenland Inuit, despite a diet

high in saturated fat and cholesterol, serum lipids , particularly

triglycerides, were significantly lower than in Danes and hypothesized

that it was the omega 3 fatty acids that were responsible

• Two families of dietary PUFA’s:

– omega 3

• Plant: alpha linolenic acid

• Marine: EPA, DPA and DHA

– omega 6

• Mechanism of action is complex, but involves inhibition of fatty acid

synthesis (lipogenesis) and stimulation of fatty acid oxidation

Omega 3 on lipid profile

Omega 3 FA Early Clinical Trials• GISSI Trial

– 11,234 Italian patients with recent MI (<3 months) and

randomized to 0.85 g/day of EPA and DHA for 3.5 years

– 21% reduction in mortality

– 44% reduction in sudden death

– Primary endpoint (death, non fatal MI and non fatal stroke(

was significantly reduced by 15%

– Results were thought to be mediated by an anti-arrhythmic

effect. Study was also criticized for its methodology

Omega 3 FA Early Clinical Trials

• JELIS Trial

– Japanese 14,981 primary prevention patients and 3664 secondary

prevention

– Group had high baseline Omega 3 FA intake

– Intervention: 1.8 mg QD of highly purified EPA to statin therapy

– 4.6 year follow up

– Incidence of major events reduced by 19%, including composite of

non fatal MI, CHD death, unstable angina and revascularization

– Benefit was seen only in secondary protection group

– ? Generalizability of the study

Omega 3

• REDUCE IT Trial

• ASCEND

• VITAL

Icosapent ethyl

• Pharmaceutical grade omega 3 fatty acid

• REDUCE-IT Trial

– High dose purified EPA –only (Vascepa) 4 GM/day

– Endpoints: CV death, non fatal MI, non fatal stroke, coronary revascularization or unstable angina

– 8,179 patients; median age 64, 71% men

– triglycerides 135-499 and LDL 41 to 100

– Prior CVD or DM

– Median follow up 4.9 years

– Total primary endpoints were reduced by 30% over placebo

• 61 per 1,000 patient years vs 89 per 1,000 patient years on placebo RR=0.7, 95% CI 0.62-0.78

• 20% reduction in CV death

• 31% reduction in MI

• 28% reduction in stroke

• Low risk of adverse events; increased risk of hospitalization for AF

ASCEND

• 15,480 patients with DM, but no CAD

• 1 GM n-3 fatty acids or olive oil placebo

• Outcomes: non fatal MI, CVA, TIA, vascular death

• 7.4 years of follow up

• No significant difference in rates of vascular

events, revascularization or death Effects of n-3 Fatty Acid Supplements in Diabetes Mellitis: N Engl J Med 2018; 379:1540-1550 DOI: 10.1056/NEJMoa1804989

VITAL Trial• 25,871 patients, men 50 and older, women 55 and older

• Primary endpoints

– Composite of MI, stroke, or death from CV causes. Secondary endpoints were

individual components of the composite

• Intervention: 1 GM QD of an omega-3 drug (Lovaza or Omacor) (or Vit D in

a separate arm of the study)

• 5.3 years of follow up

• However some secondary outcomes were promising

– MI risk 28% lower

• Greatest benefit in low consumption of omega 3 and in blacks

Marine N-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer: N Engl J Med2019; 380: 23-32 DOI: 10.1056/NEJMoa1811403

Canakinumab• CANTOS Trial

– Monoclonal antibody targeting interleukin-1 beta

– 10,061 patients with previous MI and elevated CRP (>2mg/l)

– 3 dose ranges (50,150 and 300mg) tested SQ Q3months

– Endpoints: non fatal MI, any non fatal stroke, CV death

– Showed reductions in CRP

– Only one dose (150mg Q 3 months) showed a statistically significant reduction in recurrent events

(p=0.005). There was no mortality benefit.

– Treatment was associated with higher incidence of fatal infection relative to placebo

• First drug targeting inflammation to show benefit in CV risk reduction

• Not approved by the FDA

• Cost is $73,000 per year

• QALY $6.4 million, $100,000 is considered acceptable

Anti inflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017; 377-1119-1131 DOI: 10.1056/NEJMoa1707914

Omega 3 takeaways• May benefit patients with low intake of omega 3

or African American patients

• Icosapent ethyl demonstrated to show benefit in

the highest risk patients (known disease with

elevated triglycerides)

– Dose

– Higher ratio of EPA to docosahexanoic acid

Aspirin for primary prevention

• Patients at intermediate levels of risk

• All trials showed lower than expected rates of

vascular disease events:

• ASCEND

• ARRIVE

• ASPREE

Ebers papyrus

Aspirin

Aspirin

• Acetylsalicylic acid

– A precursor to ASA is found in leaves from the willow tree and has been used for 2400 years

– First synthesized in 1853 by Charles Gerhardt

– 1899 Bayer found that it was less irritating than other salicylates in use at the time and began marketing it under the name

“Aspirin”

• NSAID

• Used to treat pain, fever, inflammation

• Used in secondary prevention for CAD and CVA

• May reduce the risk of colorectal cancer

• Mechanism

– Irreversible inactivation of cyclooxygenase (COX) required for prostaglandin and thromboxane synthesis; Nobel prize to British

pharmacologist John Robert Vane for this discovery in 1982

– Blocks formation of thromboxin A2 in platelets, which inhibits platelet aggregation for the life of the platelet (8-9 days)

– May be some other effects mediated via COX 1 and 2 that mediate inflammation; affect mitochondria; induces formation of

nitric oxide and modulates signalling through NF-KB.

Platelet Activation

ASPREE

• Adults older than 70 (>= 65 for blacks and Hispanics), free from CVD, dementia or disability

• N=19,114

• Low dose ASA (100 mg QD)

• 4.7 year follow up

• Outcome:

– Fatal CHD, non fatal MI, stroke, HF hospitalization

• ASA 10.7 events per 1,000 person-years; placebo 11.3 events per 1,000 person years HR=0.95; 95% CI 0.83-1.08

– Major hemorrhage

• ASA 8.6 events per 1,000 person-years; placebo 6.2 events per 1,000 person years. HR=1.38; 95% CI, CI 1.16-1.82

– Cancer related death

• ASA 3.1% ; placebo 2.3%; HR 1.31,95% CI 1.1-1.56

Effect of Aspirin on Cardiovascular Events and Bleeding in the Health ElderlyNEJM 2018; 379;1509-1518 DOI:10.1056/NEJMoa1805819

ARRIVE

• Men aged <55, women <60 and at moderate risk of CV

• N=12,546

• Outcome

– CV death, MI, USA, CVA or TIA

• ASA 4.29%; placebo 4.48%; HR=0.96, 95% CI, 0.81-1.13

– GI bleeding

• ASA 0.97%; placebo 0.46%; HR 2.11, 95% CI 0.79-0.97

Lancet. 2018 Sep 22; 392 (10152): 1036-1046

ASCEND• Patients with diabetes but no evidence of CAD

• N=15,480

• ASA dose 100 mg QD

• Outcome

– MI, CVA, TIA, vascular death excluding intracranial hemorrhage

• ASA 8.5%; placebo 9.6%; rate ratio=0.88; 95% CI, 0.79-0.97

– Major bleeding

• ASA 4.1%; placebo, 3.2%; rate ratio=1.29; 95% CI, 1.09-1.52

• No cancer difference in ASA vs placebo

The ASCEND Study Collaborative Group. NEJM 2018;DOI:10.1056/NEJMoa804988

Conclusions• No benefit at all

• -or-

• May have benefit in certain circumstances

• ACC:

– Should not be used at all in patients 70 years or older or in patients at

high bleeding risk

– May be considered for patients 40-70 years of age at high risk of CVD

and low risk of bleeding

• e.g. Positive coronary calcium score, strong family history, very high lipids

and statin intolerant, high ASCVD risk (>20%)

Considerations for ASA in primary prevention

• Be sure benefit outweighs risk

• Evaluate risk factors

– ASCVD risk score (greater than 20%), FH of premature ASCVD, and possibly

an elevated coronary calcium score

• Consider risk of bleeding

– Comorbidities, PUD c/b bleeding, recent ulcers, recent GIB, kidney disease,

other NSAID use

• ASA should be considered once other options have been implemented,

i.e., lipid lowering, BP reduction, and smoking cessation

• Strong family history of colon CA may favor ASA use

Rivaroxiban (Xarelto)

• Factor Xa inhibitor, inhibiting thrombin

formation

• Approved for use in 2011

• Indications include

– Stroke prophylaxis in non valvular AF

– DVT prophylaxis

– DVT/PE treatment

Rivaroxiban

• COMPASS Trial

• ASA combined with low dose rivaroxiban (2.5 mg BID)

compared with ASA alone

• Reduced CV events by 24% in patients with CAD

• Reduced CV events by 28% in patients with PAD

• 51% increased risk of major bleeding, but not fatal

bleeds or ICH

N Engl J Med 2017 Oct 5;377[14];1319-30

SGLT-2 Inhibitors

SGLT-2 Inhibitors

• Empagliflozin

– EMPA-REG Trial

• Dapagliflozin

– DECLARE TIMI 58Trial

Empagliflozin (Jardiance)

• SGLT-2 Inhibitor

• EMP-REG Outcome Trial

– 7,020 patients with type 2 DM and CAD

– Compared with placebo

• Reduced all-cause mortality over 3.1 years of follow up

• Reduced C-V mortality by 38%

• Reduced HF hospitalizations by 35%

N Engl J Med. 2015 Nov 26;373[22]:2117-28

Empagliflozin• EMPA-HEART Cardiolink 6 Trial

– Randomized trial of 97 patients with type 2 DM and CAD

– In 6 months of treatment

• Reduced LV mass by 4.71 gm vs 0.39 gm with placebo

• Systolic BP decreased 7.9 mm Hg vs 0.7 mm Hg with placebo

• Hematocrit increased by 1.91% relative to placebo

• Mechanism of benefit is unclear, but this study suggests

there is a direct effect on cardiac remodeling plus other

non cardiac mechanisms

Dapagliflozin (Farxiga)

• DECLARE-TIMI 58 Trial

– 17,160 patients with type 2 DM from 33 countries

– 7,000 with CAD

– 10,000 with risk factors for CAD

– At least 40 years of age

• MACE rate similar to placebo

• 17% lower rate of CV death, 33% hospitalization for HF

• Less robust benefit than empagliflozin

N Engl J Med 2019; 380 :347-357. DOI: 10.1056/NEJMoa1812389

CANVAS Program

• Two sister trials (CANVAS and CANVAS-R)

• 10,142 patients with Type 2 DM and kidney disease

• 100 mg QD of canagliflozin or placebo

• Primary outcome: composite of doubling of serum creatinine or death from cardiovascular cause

• Trial was event driven and stopped early

• Event rate was significantly lower in the canagliflozin group (43.2 vs 61.2 per 1000 patient years).

– 30 percent lower relative risk

– Patients in the treatment group had a lower risk of CV death, hospitalization for heart failure, MI or stroke

– The relative risk of the composite of end stage kidney disease, doubling of the serum creatinine or renal

death was 34% lower with treatment

– Rates of adverse events was similar in both groups except for an increased risk of amputation

N Engl J Med 2019; Apr 14

Use of SGLT-2 Inhibitors

SGLT-2

• Currently, empagliflozin and canagliflozin are

the SGLT-2 inhibitors indicated for the

reduction of CV events in adults with type 2

DM and established CVD

Glucagon-like Peptide-1 Receptor Agonists (GLP-1)

• Agonists of the GLP-1 receptor

• Indicated for the treatment of Type 2 DM

• Currently approved medications include:

– exenatide (Byetta) approved 2005

– liraglutide (Victoza) approved 2010

– lixisenatide (Lyxumia) approved 2016

– abliglutide (Tanzeum) approved 2014

– dulaglutide (Trulicity) approved 2014

– semaglutide (Ozempic) approved 2017

GLP-1

• GLP-1 is a peptide hormone secreted by the

enteroendocrine cells of the distal small intestine

and colon, alpha cells of the pancreatic islets and

neurons in the CNS

• It is secreted in response to nutrient ingestion

and mediates regulatory effects on glucose

assimilation and homeostasis

GLP-1 Agonists MOA

GLP-1 Trials

• LEADER

– 9,340 adults with increased cardiovascular risk (CAD, CVA, PAD, CKD>3, HF 2-3 or age > 60 with at least 1

CRF) and type 2 DM

– Liraglutide vs placebo vs 3.5 years

– Primary composite outcome: death from CV causes, non fatal MI or non fatal CVA

– Primary CV outcome was decreased relative to placebo, HR 0.87 (95% CI 0.78-0.97, P=0.01)

– Outcome was driven mostly by reduction in fatal events

• CV mortality HR 0.78 (95% CI 0.66-0.93, p=0.007)

• Total mortality (death from any cause) HR 0.85 (95% CI 0.74-0.97, p=0.02

• However, individual rates of non fatal MI, non fatal CVA and hospitalization for HF were no

different

• Theorized that benefit may be related to mechanism other than an antiatherosclerotic effect

Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.

Other GLP-1 Trials

• EXSCEL

– 14,752 high risk patients with type 2 DM

– Exenatide vs placebo

– No statistically significant benefit on CV event reduction

• ELIXA

– 6068 patients with type 2 DM and CV disease

– Lixisenatide vs placebo

– No statistically significant benefit on CV risk reduction

Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med2015;373:2247-57.

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. Am Heart J 2016;174:103-10.

GLP-1 agonists

• Currently, only liraglutide has the indication

for reduction in the risk of major adverse

cardiac events (MACE) in adults with type 2

DM and established CV disease

SGLT-2/GLP-1

• Should be considered for patients with type 2 DM and

cardiovascular disease; metformin should probably be baseline

therapy

• Will require more coordination of care between primary care and

cardiology

– When to add these meds?

– Who makes the decision?

– Monitoring of treatment?

– Answer: Probably not the cardiologist (we are not good at this!)

Hypertension Guidelines

• 2017

ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/

ASPC/NMA/PCNA

• Led by ACC and AHA

• Special care was taken to govern conflicts of

interest and relationships with industry

Important Points• Recognize patterns of blood pressure abnormalities

– “Masked” HTN (aka ‘reverse white coat HTN’):

• Defined as normal BP in the office, but elevated outside

• Affects 15-25% of the population

• Similar risk for CV disease compared with those with sustained HTN

• Suspect it in patients with target organ damage of HTN, but with

normal BP

• More common in African Americans, DM and chronic renal failure

• Gold standard for diagnosis is ambulatory BP monitor

BP Patterns

Office/clinic/Healthcare setting

• No HTN

• HTN

• No HTN

• HTN

Home/Nonhealthcare setting

• No HTN

• HTN

• HTN

• No HTN

Normotensive

Sustained HTN

Masked HTN

White Coat HTN

Paul K. Whelton et al. JACC 2018;71:e127-e248

2018 American College of Cardiology Foundation and the American Heart Association, Inc.

BP classification

• Normal, elevated, stage 1 and stage 2

• Prehypertension and high normal are no

longer used

Overview of BP Diagnosis and Management

Paul K. Whelton et al. JACC 2018;71:e127-e248

2018 American College of Cardiology Foundation and the American Heart Association, Inc.

Theres an APP for that

HTN Take aways

• Non pharmacologic therapy will be the recommended treatment

for the majority of patients with newly diagnosed HTN

• Formal assessment of risk drives treatment thresholds and targets.

• For most patients, BP goal is 130/80 or less

• Four agents are recommended: thiazides, calcium channel

blockers, ACE and ARB, with thiazides being the first line agents

• Concepts of prehypertension and high normal are removed

HTN

• Renal artery denervation

– RF Ablation

– US ablation

• Radiance II Trial

– Patients 18-75 with either controlled BP on meds, or

uncontrolled and on meds are eligible

RADIANCE Trial

PCSK-9 Inhibitors

• Evolocumab (Repatha)

• Alirocumab (Praluent)

• Both given by injection 1-2 per month

• Average LDL reduction of 50-60% on monotherapy

• Indications

– CAD: Inability to achieve goals of treatment on maximal therapy or

maximally tolerated therapy

– Primary prevention: LDL>190, usually with some evidence of familial

hypercholesterolemia (FH), and inability to achieve goals with maximal

therapy or maximally tolerated therapy

PCSK 9 MOA

Trials• FOURIER, SPIRE

• ODYSSEY OUTCOMES

• 18,924 patients with ACS1-12 months earlier

– LDL of at least 70

– On statin and receiving maximum or maximum tolerated dose

– Treatment with alirocumab (Praluent) 75 mg Q 2 weeks to adjust LDL to between 25 and 50 mg/dl

– Primary endpoint: composite of death from CAD, non fatal MI, fatal or non-fatal ischemic stroke or USA

requiring hospitalization

• Results

– Median follow up 2.8 years

– Primary endpoint alirocumab 903 (9.5%) vs placebo 1052 (11.1%) (HR 0.85; 95% CI 0.78-0.93; p<0.001)

– Absolute benefit was greater in patients with LDL of greater than 100

– Incidence of adverse events was similar in both groups except for local site reactions (3.8% treatment vs

2.1% placebo)

PCSK 9• Advantages

– Clinically proven to reduce LDL and subsequently

reduce CV events, either alone or in addition to

standard therapy

– Fairly simple and convenient to use

– Low incidence of SE

PCSK 9• Disadvantages

– Expense

• Initially both were about $1,400/mo ~ $14,000/year

– Not cost effective at this price

• More recently

– Both have reduced prices to about $450/month

– Appears to be cost effective for the highest risk patients

• Hoops to jump through

– Paperwork demonstrating prior treatments

• Usually need atorva, rosuvastatin and ezetimibe trials

• LDL levels

• Document failure to achieve goals on treatment or intolerance

• 80% of plans still require cardiology/endocrin/lipid doc to sign off for insurance approval

TAVR

• Trans catheter aortic valve replacement

• Indicated for intermediate and high risk

patients with severe AS

• PARTNER 3 and Evolut Low Risk Trials

Partner 3• 1,000 patients, mean age 73 with severe AS and a mean STS score of 1.9% (low risk)

• Randomly assigned to TAVR with a Sapien 3 valve or surgical valve replacement

• Outcomes at 1 year:

– Death/stroke/rehospitalization

• TAVR 8.5% SAVR 15.1%

– Mortality

• TAVR 1% SAVR 2.5%

– All stroke

• TAVR 1.2% SAVR 3.1%

– Death or disabling stroke

• TAVR 1% SAVR 2.9%

– Rehospitaliztion

• TAVR 7.3% SAVR 11%

• Similar results in Evolut Low risk Trial, although it showed higher rates of AR and pacemaker

implant than the surgical gruop

Mack M, et al. N Engl J Med 2019; doi: 10.1056/NEJMoa 1814052

TAVR

• About 50% of patients in the US are getting TAVR vs SAVR,

and this is expected to grow

• Questions remain regarding long term durability

• Factors favoring SAVR:

– Younger, < 60

– Bicuspid aortic valves

– Other valve, CAD or aortic disease

– Severely calcified annulus

Summary

• Exciting time in cardiovascular disease, especially prevention

• More effective tools for risk assessment.

• Use of imaging for assessing presence or absence of disease

• Renewed focus on lifestyle

• New and effective therapeutics available or in the pipeline

• Need for coordination between cardiology and primary care to

provide maximum benefit for the patient