Prevention and treatment of

cardiovascular diseases and

complications

INDTEL190338 22nd Jan 2019

PATH= Prevention And Treatment of Hypertension complications
Holistic Hypertension Management
-The PATH Ahead

INDTEL190338 22nd Jan 2019

PATH= Prevention And Treatment of Hypertension complications
 Mr. “X”, a 50-year-old male...
CASE PROFILE

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 Case 1

Clinical Presentation
Presented with...
 Giddiness since 15 days, on and off, more evidently seen in the morning time, reduced on
lying down flat
 Occipital headache for past 1 week - partly relieved by analgesics
 Blurring of vision - 2 episodes a day ago, persisted for a few seconds and automatically
subsided on its own
 No history of chest pain/palpitations/loss of consciousness

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 Case 1 Contd…….

History
Medical History
 Hypertensive and diabetic since 5 years. On amlodipine (5 mg OD) and metformin (500 mg BD)
 Not on regular medical follow-up since past 1 year
 History of having undergone an appendicectomy last year

Family History Personal History

 Father, 80 years old, a known case of CAD  Not a known smoker
and on medication  A known alcoholic since 20 years, takes in
moderation (once in 15 days)

CAD = Coronary artery disease

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Burden of High Blood Pressure
- Increasing trend in hypertension prevalence despite
A global public awareness and improved treatment1
health issue
- Uncontrolled BP among 47% of adults aged over 20 years1

Only 40.3% of the Indian population achieved blood

- Most of the time, has no obvious symptoms
Silent Killer pressure goals.2
- 50% of people remain undiagnosed2

Dreadful - Major risk factor for CV, cerebrovascular and CKD1,3

consequences
- Cause for premature morbidity and mortality3

BP = Blood Pressure; CV = Cardiovascular; CKD = Chronic Kidney Disease

1. Hamrahian SM.
ProprietaryCurr
andHypertens
confidentialRep. 2017;19(5):43. 2. http://www.heart.org. 3. Saiz LC, et al. Cochrane Database Syst Rev. 2018. 
— do not distribute
2. KP Suresh Kumar et al. clin of of htn, 2018; 3 26-35
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 Case 1 Contd…….

Clinical Examination
General Physical Examination Systemic Examination

 Bilateral pitting pedal edema ++  CVS: S1, S2 heard, no murmurs

 No pallor, icterus, cyanosis or  Respiratory: NVBS
lymphadenopathy  Per abdomen: Soft, no hepatosplenomegaly.
 Afebrile Bowel sounds heard
 CNS: Oriented to time, place and person.
 Pulse: 95 bpm
Cranial nerves appear bilaterally intact, sensory
 Respiratory rate: 15 times/min
and motor system appear apparently normal
 BP: 150/98 mmHg, left upper limb, supine
 Fundoscopy: Grade 1 retinopathy
position

CVS = Cardiovascular System; NVBS = Normal Vesicular Breath Sounds; CNS = Central Nervous System

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Hypertension Definition Evaluation
1980s and 2003 2007 2017
early 1990s Upto to 1993
(JNC 7) (ESC/ESH 2007) (ACC/AHA 2017)

Hypertension; BP reduced to BP 120–139/80–89 mmHg as a BP 130–139/85–90 mmHg as a

BP >160/95 ≥140/90 mmHg1 pre-hypertension +1 high normal BP1
mmHg 1
BP >130/80 mmHg
Rationale behind >130/80 mmHg as Hypertension reclassified as
 Established link between the level of BP (at SBP of 115 mmHg) and the risk hypertension2
of CV disease3
 Risk of CV events^ and renal failure begins even low BP of 110–115/70–75 mmHg

^CV events: Stroke, MI, sudden death, HF and peripheral artery disease (PAD)
JNC = Joint National Committee ; ESC = European Society of Cardiology ; ESH =European Society of Hypertension ; ACC = American college of cardiology; AHA = American heart association

1. Jarraya F. Adv Exp Med Biol. 2017;956:117-127.  2. Pradhan A. Heart India. 2017;5(4):139–144. 3. Wander GS, et al. Circulation. 2018;137:549–550.
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 Case 1 Contd…….

Investigations
Laboratory Radiological
Hematology: Hb 13 g%, TC 9000 cells/cumm; DC = poly  ECG: Left ventricular strain pattern
70, L 18, M 11, E 1
Blood urea: 27 mg/dL  2D ECHO: EF 69%
Serum creatinine: 1.2 mg/dL  Treadmill test negative for inducible
Lipid profile: TC 198 mg/dL, HDL 37 mg/dL, LDL 125
ischemia
mg/dL, TG 152 mg/dL
FBG 129 mg/dL, PPBG 172 mg/dL, HbA1c 7.7 mg/dL
Urine routine: Protein +
UACR: 122 mg/g of creatinine

TC = Total count; DC = Differential count; L -= Lymphocytes; M = Monocytes; E = Eosinophils; LAD = Left anterior descending
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 Risk Assessment – 10-year ASCVD risk calculator

Individual ASCVD risk is based on the 10-year Framingham Risk Score1

10-year Identifies patients in higher-risk groups who are likely to have greater net benefit with
ASCVD risk antihypertensive and statin therapy2

Tabulation is based on scoring points for

parameters: age, smoking , TC, HDL-C, Recommendation3
To guide BP threshold for drug therapy4
SBP
Type of risk Risk (%)
High ≥20%
Intermediate 10 –20%
Low <10%

ASCVD= Atherosclerotic cardiovascular disease

1. Available from: http://www.sciencedirect.com/topics/medicine-and-destry/framingham-risk-score. Accessed on Jan 2, 2019. 2. Lloyd-Jones DM, J Am Coll Cardiol. 2018.
3. Garg N, et al. Indian Heart
Proprietary Journal. 2017;69:458–43.
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Whelton PK, et al. Circulation. 2018;138(17):e426-e483.
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 Risk Assessment – Heart Age/Vascuar Age

Measurement of individual current heart age when compared to

actual (ideal) age1
Heart Older age indicates the risk of CV complications than current age1
Age/Vascula
r Age Predicts risk of CV complications (HF or stroke ) in the next 10 years`

Motivates patients to reduce risk of developing CV complications by changing lifestyle

(Eating a healthy diet and doing physical activity)2
Tabulation is based on scoring points
for the parameters of age, smoking,
plasma total and HDL cholesterol and
SBP3
Vascular age Age New Zealand and the UK are the countries that most
High ≥80 clearly link heart age to clinical medication guideline 3
Intermediate 30-80
Low <30
HF = Heart Failure
1. Bonner C, et al. BMC
Proprietary andCardiovasc Disord.
confidential — do2018;18(1):19. 2. Lopez-Gonzalez AA, et al. Eur J Prev Cardiol. 2015;22(3):389–396. 3. D'Agostino RB Sr, et al. Circulation. 2008;117(6):743–53.
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 Risk Assessment – Stroke Risk Calculator
The individual stroke risk is based on the Framingham equations

It may help to identify persons at substantially increased stroke risk and to take
Stroke risk the necessary protective measures

Recommendation2
Tabulation is based on scoring points for the
parameters: Ethnicity, gender, age, use
of antihypertensive therapy, SBP, DM,
cigarette smoking, presence of CV
disease, changes in ECG, H/O of HF
and sedentary lifestyle
High ≥20%
Moderate 10 – 20%
Low <10%
High ≥20%
HF= Heart failure; DM = Diabetes mellitus; ECG = Electrocardiogram
1. Available from: http://www.medindia.net/pa?ents/calculators/stroke-risk-calculator.asp.
Proprietary and confidential — do not distribute Accessed on July 27, 2018. 2. Kavousi M, et al. JAMA. 2014;311(14):1416-1423.
3. Bonner C, et al. BMC Cardiovasc Disord. 2018;18(1):19. Proprietary and confidential – do not distribute
 Risk Assessment – Kidney Failure Risk Calculator
To determine the individual 2-and 5-year probability of treated kidney failure
(dialysis or transplantation) for patient with CKD stage 3 to 5.

Kidney
Failure Risk The individual risk of kidney failure is based on the Kidney Failure Risk Equation

Tabulation is based on scoring points

for the parameters: Age, gender,
region, creatinine,
eGFR & ratio of urine
albumin:creatinine
Type of risk Risk (%)
High 15%
Intermediate 5 – 15%
Low 0 – 5%

eGFR = estimated glomerular filtration rate; CKD = Chronic kidney disease

Available from: http://kidneyfailurerisk.com/.
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do notondistribute
July 27, 2018.
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 Case 1 Contd…….

Risk Calculator – Findings Diagnosis

• Uncontrolled hypertension
31. 18% 8% (stage 2) and type 2 diabetes
High risk Low risk mellitus with high ASCVD risk

>80 years Stage 2 CKD

High vascular age Failure risk @ 5 yrs 0.1%

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Major Challenges - In Indian Context

BP threshold and BP target

Guidelines recommend BP threshold remains a matter of debate1,2
lower BP threshold

Fail to achieve BP target 25% of treated patients failed to achieve BP goal3

(<140/90 mmHg)

Guidelines recommend Target BP in the elderly and in those with co-morbidities a

lower BP goal major critical issue4

Ironically, goal recommended by IHG are not yet followed fully1

IHD = Indian hypertension guidelines
1. Wander GS, et al. Circulation. 2018;137:549–550. 2. Wander GS, et al. CardioPulse . 2018:3012–3016. 3. Nagappa B, et al. J Family Med Prim Care 2018;7:81-6.
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4. Hiremath J, et al. Journal of Clinical and Diagnostic Research. 2016;10(12):25–28.
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What is the NEED???
Adopt and enforce screening and diagnosis programs on a massive scale
and increase awareness and access to medical care1

Implementation of accurate BP measurement & appropriate

treatment to avoid hypertension-related serious complications1,2

Obtaining a target goal BP is crucial to prevent poor outcomes such as CV

disease, kidney failure and stroke 1,2

It is prudent to focus on multiple risk factors while treating

hypertension3
A combination therapy with multiple agents are important; appropriate
dosage and adherence to the therapy is crucial3

Need for constant motivation and one-to-one level education at

frequent intervals to ensure better adherence4
1. Wander GS, et al. Circulation. 2018;137:549–550. 2. Expert group. Journal of Clinical and Diagnostic Research. 2018;12(1):1–4. 3. Bharatia R, et al. J Assoc Physicians India.  2016;64(7):14-21.
4. Sharma T, et al. JIACM 2014; 15(1): 26-9
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 Case 1 Contd…….

Treatment
 The patient was started on:
 Telmisartan tablet 40 mg OD along with chlorthalidone 12.5 mg
 Glimepiride tablet 1 mg OD along with metformin and a strict advice on lifestyle modification
was stressed upon
 Aspirin tablet 75 mg OD
 Advised to do home-based BP monitoring using an electronic BP recording machine
 Was asked to come for follow-up after 15 days

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 Case 1 Contd…….

Follow-up

At 1 Month
BP: 136/80 mmHg

Telmisartan +
Chlorthalidone

At 15th day At 3rd month^

• Symptoms subsided BP: 122/80 mmHg
• BP: 152/84 mmHg FBG: 102 mg/dL
HbA1c: 6.5%
UACR : 32 mg/g Cr
FBG = Fasting blood glucose; UACR = Urine albumin creatinine ratio
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Practice Point– BP in ASCVD risk
Universal BP targets are difficult to recommend since different BP levels are associated
with different CV diseases1

BP goals should be defined according to the risks of all possible CV diseases 1

Achieved SBP <120 mmHg was associated with an increased risk for CV events except for
MI, stroke and all-cause mortality2

BP target (<130/80 mmHg) could be appropriate for some people with CAD, previous
MI, stroke or CAD equivalent3

MI = Myocardial infarction; CAD = Coronary artery disease

1. Dreyfuss-Tubiana C, et al., J Thorac Dis. 2017;9(7):1835-1838. 2. Kahan T. www.thelancet.com Published online. April 5, 2017. http://dx.doi.org/10.1016/S0140-6736(17)30935-2. 3.
Saiz LC, et al. Cochrane Database Syst Rev. 2018.
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 Therapy Recommendations - HTN with ASCVD Risk
ASCVD risk <10%
Should be managed with nonpharmacological therapy and a repeat BP
evaluation within 3 to 6 months
Elevated BP or stage 1 Therapy Recommendations - HTN with ASCVD Risk
HTN (130–139/80–89
mmHg)
ACC/AHA

Managed with a combination of nonpharmacological and

antihypertensive drug therapy
ASCVD risk of 10% or higher

Stage 2 HTN  Nonpharmacological therapy and BP-lowering medication

(140/90 mmHg)  Consider initiation of 2 antihypertensive agents of different classes

ASCVD = Atherosclerotic cardiovascular disease

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Whelton and confidential — do not distribute
PK, et al. Circulation. 2018;138(17):e426-e483.
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 Telmisartan and Chlorthalidone
TELMISARTAN CHLORTHALIDONE (CTD)

Composite of CV death, SBP by 15 mmHg; (From 142 to

Reduces
Reduces

MI and stroke by 13%1 127 mmHg; p<0.0001)

45%
stroke
49%
CVE
CTD –
Reduces CV
complications
72%
CHF
74%
MI
1. Akhrass PR, et al. Vascular Health and Risk Management. 2011:7 677–683.
2. Dorsch MP, et al. Hypertension.
Proprietary 2011;57:689–694.
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 Telmisartan and Chlorthalidone
Increases FMD by 48% -
Improves endothelial function 2 Hypolipidemic effect and
improves the carbohydrate
Consistent BP control over metabolism3
24 hrs - Protects early morning
BP rise on CVD risk1
ARB (Telmisartan)
+
Thiazide
(Chlorthalidone)
Reduces central SBP – Pleiotropic properties -
An additional mechanism of Effectively lowers CV events7
CV protection4
Long-acting agents - superior
24-hr BP control5 Reduces BPV6
FMD = Flow mediated dilation; BPV = Blood pressure variability

1. Parati G, et al. Hypertension Research. 2013;36,:322–327. 2. Akhrass PR, et al. Vascular Health and Risk Management. 2011:7 677–683. 3. Somesekhar V, et al. Evid.
Based Med. Healthc. 2016; 3(34), 1635–1637. 3. 4. Yugar LBT, et al. J Clin Hypertens (Greenwich).. 2018;20(1):133-135. 5. Dorsch MP, et al. Hypertension. 2011;57:689-694.
6. Morita, et al. Lancet.2017;389:153.
Proprietary and confidential —7. do
Mehta
notetdistribute
al. Clinical Hypertension. 2018;24:4 .
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 Secondary prevention

INDTEL190338 22nd Jan 2019

PATH= Prevention And Treatment of Hypertension complications
Estimates and Trends of Coronary Heart Disease
in India
Estimates and trends of CHD cases across Projected burden of CV disease in India by
various age groups in India1 the year 20202

700 60-69 years

CHD cases (in lakh)

600 50-59 years CVD will be the largest cause

40-49 years of death and disability in India
500
400
300 DALYs due to CVD Deaths
200 CVD • 4.8
100 • 43.5
million
0 million
2000 2005 2010 2015

CHD:Coronary heart disease; CVD; Cardiovascular disease

1. Indrayan A. Reports of the National Commission on Macroeconomics and Health. Ministry of Health and Family Welfare, India 2005. 24
2. Nag T, Ghosh A. Cardiovasc Dis Res. 2013 Dec; 4(4): 222–228.
Case (A 42-Year-Old Woman with Diabetes): Follow
up After 1 Year
• A lady came to the clinic with complaints of chest pain.
• She is a known case of diabetic and is on lipid lowering
therapy
• Her chest pain appears after 10-15 min of her aerobic
exercises.
• Pain subsides with rest.
• Her ECG findings and other clinical findings and history
confirmed a diagnosis of stable angina

How can the patient be managed now? What is the right statin dose?
Case (A 42-Year-Old Woman with Diabetes): :
Discussion and Management
How can the patient be managed now?
• She was asked to continue with teneligliptin 20 mg plus metformin 1000 mg twice daily and
telmisartan 20mg daily.
• She was given apirin 325 mg; nitroglycerine (SOS); Ranolazine 500 mg twice daily, atorvastatin 80 mg
and fenofibrate 100 mg

According to ADA guideline1

• High intensity statin is recommended for diabetes patients who present with ASCVD

• According to the ACC/AHA 2013:2

• High intensity statin are recommended for secondary prevention in patients with diabetes

What should be the right dose statin?

• High-intensity statin: Atorvastatin 40–80 mg or rosuvastatin 20–40 mg

ACS: acute coronary syndrome; ASCVD: Atheroscleroic cardiovascular disease; ADA:
American Diabetes Association; ACC/AHA: American College of Cardiology/American Heart
Association;
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1. ADA. Diabetes Care. 2017;40(Suppl. 1):S75–S87.
Dyslipidemia: A Major CV Risk Factor for MI

Elevated apolipoprotein B/apoA1 ratio was associated with a fourfold

increased risk of myocardial infarction.
Apo: Apolipoprotein; CV: Cardiovascular; MI: Myocardial infarction; OR: Odds ratio.
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Yusuf S, et al. Lancet. 2004;364:937–952.
Dyslipidemia Pattern in India Is Strikingly Different
Compared to Global Population

Atherogenic dyslipidemia’,

Atherogenic dyslipidemia is a common pattern of dyslipidemia in South

Asian populations
HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; VLDL: Very low-density
lipoprotein cholesterol; TG: Triglycerides.
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Chandra KS, et al. Indian Heart J. 2014;66 Suppl 3:S1-51.
Secondary Prevention of CAD: An Overview

• Comprehensive risk factor management in patients with atherosclerotic

vascular disease reduces cardiovascular risk as assessed by
• improved survival,
• reduced recurrent events,
• need for revascularization procedures, and
• improved quality of life.

Encompasses those with:

• Established coronary and other atherosclerotic
vascular disease including peripheral arterial disease,
atherosclerotic aortic disease and carotid artery
29
disease
Gaps in Secondary Prevention
There is slow transmission of knowledge of current evidence-based
strategies in primary and secondary care in India1
Physician level Individual patient level2

• Lack of awareness about prevention guidelines 1 • Lack of motivation and commitment

• Lack of motivation1 • Failure to realize seriousness of problem
• Lack of continuity of care2 • Low socioeconomic status
• Lack of understanding of patient’s requirements 2 • Significant co-morbid conditions
• Lack of focus on lifestyle changes 2 • Costs
• Prescription of complex regimens 2 • No insurance cover
• Low clinical referrals2 • Lack of quality information
• Fixed clinical perceptions2 • Failure to sustain lifestyle changes
• Failure to explain benefits and side effects 2 • Confusing messages from multiple stake-holders
• Overtreatment2

CAD: Coronary artery disease

1. Matthias AT, Lokunarangoda NC, Ekanayaka R. BMC Medical Education. 2014, 14:113. 30
2. Sharma KK, Gupta R, Agrawal A, et al. Vasc Health Risk Manag. 2009;5:1007-14.
Lack of Long Term Compliance to Medications
Less than 50% of patients with CAD are compliant to their prescribed
medications
Findings of PURE study

Less
Current educated Rural
smokers inhabitants

Women Illiterates

Medication
Younger
non Poor
individuals
compliance

More than 80% of patients with pre-existing stroke or CHD in South Asia were not on any drug
therapy at a median of 4 years after diagnosis

1. Desai NR, Choudhry NK. Curr Cardiol Rep. 2013;15:322.

31
2. Gupta R, Islam S, Mony P, et al. Eur J Prev Card. 2015; 22(10):1261–1271.
Cut-off Values for Dyslipidemia for Secondary CAD Prevention

Risk factor AHA/ACCF Guidelines1 Indian Guidelines2

• Treatment with statin

therapy • All patients with
established atherosclerotic
• LDL-C of <100 mg/dL;
vascular disease should be
• For very high-risk on statin therapy
patients* <70 mg/dL
• If triglycerides are ≥ 200 • LDL-C target should be <70
Dyslipidemia mg/dL with at least 50%
mg/dL, non–HDL-C reduction from the
should be <130 mg/dL;
baseline
• For very high-risk
• Non-HDL-C target should
patients, non–HDL-C
be <100 mg/dL
<100 mg/dL is
reasonable

*Presence of established CVD plus (1) multiple major risk factors (especially diabetes), (2) severe and poorly controlled risk factors (especially
continued cigarette smoking), (3) multiple risk factors of the metabolic syndrome (especially high triglycerides ≥200 mg/dL plus non–HDL-C ≥130
mg/dL with low HDL-C ,40 mg/dL), and (4) patients with ACSs

1. Smith Jr. Circulation. 2011;124:1-16.

2. Chandra KS, Bansal M, Nair T, et al. Indian Heart J. 2014;66 Suppl 3:S1-51.
Secondary Prevention Statin Trials
Trial Population Statin; duration of follow up Efficacy against CHD Efficacy
against stroke

TNT1 Stable CHD Atorvastatin 10 mg/day vs. 80 No difference in total mortality but significant reduction in Yes
mg/day; 4.9 y primary combined endpoint, fatal and nonfatal MI and
major coronary event

IDEAL1 Prior history of MI Simvastatin 20 mg/day vs. No significant lowering of primary combined endpoint; no No
atorvastatin 80 mg/day; 4 y significant decrease in any coronary event

MIRACL2 ACS Atorvastatin 80 mg/day vs. Pb; Significant reduction in primary composite end-point of Yes
16 wks composite of death, nonfatal acute MI, cardiac arrest with
resuscitation, and recurrent symptomatic MI requiring
hospitalization

PROVE IT- ACS Pravastatin 40 mg /day vs. Significant reduction in the hazard ratio for death or major No
TIMI 223 Atorvastatin 80 mg /day; 36 CV event and death due to CHD, MI or revascularization in
mo the atorvastatin group

AVERT4 Stable CAD advised Atorvastatin 80 mg/day vs. Significant reduction in the incidence of ischemic events Not
percutaneous percutaneous with atorvastatin compared to percutaneous assessed
revascularization revascularization;18 mo revascularization

ACS: Acute Coronary Syndrome; CHD: Coronary heart disease; Pb: Placebo; IDEAL: Incremental Decrease in Clinical Endpoints Though Aggressive Lipid Lowering; LDL-C: low
density lipoprotein cholesterol; MI: myocardial infarction; TNT: Treat To New Targets; MIRACL: Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering ; PROVE IT-
TIMI 22:PRavastatin Or atorVastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22; AVERT: Atorvastatin VErsus Revascularisation Treatment ; CAD;33
Coronary artery disease 1. Chandra KS, Bansal M, Nair T, et al. Indian Heart J. 2014;66 Suppl 3:S1-51. 2. Schwartz GG, Olsson AG, Ezekowitz MD, et al. JAMA. 2001;285:1711-1718. 3.
Cannon CP, Braunwald E, McCabe CH, et al. N Engl J Med. 2004350(15):1495-1504. 4. Pitt B, Waters D, Brown WV, et al. N Engl J Med. 1999;341:70-76.
High-dose Statin Therapy in Patients with
Stable Coronary Artery Disease (2/2)

High-dose statin therapy could have reduced

MCVE risk by 4% with an NNT of 25 to prevent
one MVCE during 5 years. Residual MCVE risk
will however be 14%.

Estimation of the incremental treatment effect of high-dose versus usual-

dose statin therapy in individual CAD patients enables selection of high-risk
patients that benefit most from aggressive therapy

CAD; Coronary artery disease; MI: Myocardial infarction; NNT; Number needed to treat; MCVE; Major cardiovascular event

34
• Dorresteijn JAN, Boekholdt M, van der Graaf Y, et al. Circulation. 2013;127(25):2485-2493.
Safety of High-dose Statins: Relevance to
Indian Population (1/2)
Benefits1 vs. Risks1,2

• Additional reduction in • Statistically significant

MI by 16% and stroke by increased risk of
18% than low-dose myopathy, elevated
statins transaminases, new
onset diabetes
• Additional 25% relative
reduction in all-cause • Increased drug
mortality than low dose discontinuation
statins

MI; Myocardial infarction; ACS; Acute coronary syndrome; IRIS; Investigation of Rosuvastatin in South Asian Subjects;
1. Josan K, McAlister FA. Vasc Health & Risk Manage 2007;3(5):615-627.
35
2. Menon AS, Kotwal N, Singh Y, et al. Indian J Endocrinol Metab. 2015 Sep-Oct; 19(5): 546–553.
Safety of High-dose Statins: Relevance to
Indian Population (2/2)
Relevance Absolute CV risk is higher in Asian countries
in Indian/ like India, hence aggressive lipid lowering is
more relevant1
Asian
Large studies (DISCOVERY-ASIA and IRIS)
populatio have shown that high-dose statins are
n safe and well tolerated in Asian
population
The 1
CURE-ACS trial performed in Indian
subjects has shown that atorvastatin 80 mg
was more effective but as safe and well
tolerated than atorvastatin 40 mg2
MI; Myocardial infarction; ACS; Acute coronary syndrome; IRIS; Investigation of Rosuvastatin in South Asian Subjects;
1. Menon AS, Kotwal N, Singh Y, et al. Indian J Endocrinol Metab. 2015 Sep-Oct; 19(5): 546–553.

2. Kostner K. J Clin & Preventive Cardiol 2012;1:24-26. 36

3. Kaul U, Varma J, Kahali D, et al. J Assoc Physicians India. 2013 Feb;61(2):97-101.
 Heart rate and
cardiovascular mortality

INDTEL190338 22nd Jan 2019

PATH= Prevention And Treatment of Hypertension complications
 Clinical Consequences of High Heart Rate

Heart Rate
>84 BPM at Increase of 40
rest Elevated risk for beats/min >Twofold higher
CHD all-cause
mortality

≥90 beats/min ≥90 beats/min

on admission 41% total on admission 24% severe
mortality at 1 heart failure
year post-MI

Singh BN. Increased heart rate as a risk factor for cardiovascular disease. European Heart Journal
Supplements.2003;5:G3—G9
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 Overall Mortality vs. Cardiovascular mortality with elevated
Heart Rate

Elevated
HR

Predominantly responsible
for Cardiovascular mortality

Hjalmarson A. European Heart Journal Supplements

(2007) 9 (Supplement
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 Benefits of heart rate reduction

Average
Average human human
heart beat: 29 ×heart beat: 100,800
108 beats/lifetime times/day
(80 years of life1 on average)1
(100,800×365=36792000
36792000×80=29 × 108 beats/lifetime)

For every heart

Life time beat,needed:
energy 300 mg of Adenosine
880,000 kg of ATPTriphosphate
(80 years of life(ATP) is needed
on average) 1
1

(300 mg×29 × 108 beats/lifetime=880,000 kg of ATP)

If heart beat is reduced from 70 to 60 bpm, life expectancy increases from 80 to 93.3
years1
A decrease of 10 bpm results in saving of about 5 kg ATP in a day.1

Life expectancy is inversely related to the resting HR. An increase in the resting
HR may
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do not increase risk of Heart Failure (HF) or sudden cardiac death 2
 Role of HR in myocardial ischemia

An increase in HR, in the later stages of atherosclerosis may cause plaque

rupture resulting in coronary thrombosis
Br Med Bull. 2009;90:71-84. doi: 10.1093/bmb/ldp016. Epub 2009 May 27.
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 Controlling HR is key factor in management of stable angina

An increase of HR determines several pathophysiological changes leading to

adverse cardiac events:
 Endothelial dysfunction and increase of oxidative stress
 Plaque instability
 Increased myocardial oxygen consumption
 Reduction of diastole duration with consequent reduction of coronary perfusion
 Remodeling and hypertrophy of left ventricle
 Reduction of left ventricular filling duration and
 Decrease of myocardial contractility1

HR reduction is the primary consideration to be made for the symptomatic

control in patients with stable angina. A target HR is 55–60 bpm. 2
1. Contemp Clin Trials Commun. 2016;4:58-63. doi: 10.1016/j.conctc.2016.06.003.
2. Proprietary
Available from: https://www.guidelinesinpractice.co.uk/cardiovascular/controlling-heart-rate-is-key-when-managing-stable-angina/311313.article.
and confidential — do not distribute
Accessed on 3rd August, 2018.
 Resting Heart Rate as a Predictor for Left Ventricular Dysfunction and Heart Failure
Multi-ethnic Study of Atherosclerosis

For every 1 beat/min increase in

resting heart rate, a 4% greater
adjusted relative risk for incident
heart failure (hazard ratio: 1.04;
95% CI: 1.02–1.06; p<0.001) was
observed.

HR: Heart rate

Opdahl A, et al. JACC. 2014;63:1182–1189.

 Treatment of stable angina pectoris by ivabradine in every day
practice: The REDUCTION Study

 Multicentre study
 to evaluate the efficacy and safety of ivabradine in everyday routine practice

HR was reduced by 12.4 ± 12.2 beat/min with ivabradine

REDUCTION
Study Efficacy of ivabradine for HR reduction
85 82.9
patients with 80
stable angina pectoris

HR (bpm)
(n=4,954)  75
P<0.0001 70.4
70

Treatment: Ivabradine 65
Follow-up: 4 months 60
HR before HR after 4m

KösterProprietary
R, Kaehler and
J, Meinertz T, et—
confidential al.do
Amnot
Heart J. 2009;158(4):e51-57. doi: 10.1016/j.ahj.2009.06.008.
distribute
 Ivabradine in the management of coronary artery disease with or without
left ventricular dysfunction or HF: BEAUTIfUL study
International, multicentre, randomized, double-blind, placebo-controlled, phase 3 trial with subjects of LV
ejection fraction,40% and heart rate ≥60 bpm were included. The presence of angina at baseline was
determined by New York Heart Association (NYHA) class II or III
86 % on background BB Ivabradine favoured all-cause mortality, reduction in risk
for hospitalization for acute MI
Ivabradine arm Placebo arm
12
BEAUTIfUL 10
10 8.7
study (n=1507) 8.3

Event rate (%)

8 7.4

6
p=0.41
4 p=0.41
2 1.2
Ivabradine 0.3
Placebo (n=773) 0
(n=734)
All-cause mortality CV death Death due to acute MI

FerrarProprietary
R. European Heart
and Journal —
confidential Supplements.2015;17
do not distribute (SupplG):G24–G29.
 Elevated Heart rate and myocardial Infarction

Mortality at 6 months of follow-up in patients with

acute myocardial infarction: The GISSI experience
An Acute Myocardial Infarction:

• Heart rate –a more powerful

predictor of later mortality than
assessment of left ventricular
function after arrival in hospital

Proprietary
Hjalmarson and confidential
A. European — do not
Heart Journal distribute (2007) 9 (Supplement F), F3–F7
Supplements
 Elevated Heart rate and Progression of Heart Failure

Considered to be a
predictor of poor
prognosis

Associated with increased

systemic inflammation and Significantly
endothelial dysfunction associated with CV death
in HFpEF

Elevated
Heart Rate

Takada T, Sakataand
Proprietary Y, Miyata S, et al.
confidential — Eur J Heart
do not Fail. 2014 Mar;16(3):309-16.
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 Benefits of Heart Rate Reduction in Heart Failure

Elevated heart rate is a modifiable risk factor in heart failure, and reducing
heart rate improves prognosis in these patients.

Ferrari R, et al. Nature Rev Cardiol. 2016;13:493–501. 

 Failure to reach the target dose with beta-blockers:
IMPACT RECO III

• Study included 1919 outpatients, with NYHA class II-IV HF and a left ventricular ejection fraction <40%.

Patients achieving target doses of beta-blockers

50 47

40
Percent (%)

30

20 18

10

0
Target dose Atleast 50% of tagret dose

de Groote P, Isnard
Proprietary R,confidential
and Assyag P, et—
al.do
Eur J Heart
not Fail. 2007;9(12):1205-1211.
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 Ivabradine effectively reduces the heart rate in patients
with HF who were previously on beta-blocker therapy
By using the SHIFT database, the present study compared the characteristics of patients by baseline beta-
blocker status.

The results had shown that ivabradine showed a notable decrease in the primary
endpoints like CV death and HF hospitalization (p=0.012) in all subgroups with<50%
of target beta-blocker dose (along with no beta-blocker).
Even with an increase in beta-blocker dosage, there was no disparity in the
treatment outcomes (p=0.35).

In patients whose heart rate was >70 bpm, addition of ivabradine to the beta-
blockade (as well as among those who cannot tolerate beta-blockade), was
proved to be favorable.

Proprietary
Swedberg and confidential
K, Komajda M, Böhm— M,doetnot
al. distribute
J Am Coll Cardiol. 2012;59(22):1938–1945.
Early Co-administration of Ivabradine and Beta-blockers Is Beneficial

At 1 year, heart rate ETHIC-

HFETHIC-
remained significantly
HF
lower in the
interventional group
than the control group

All patients in the

interventional
group had a heart
rate of <70 bpm at
1-year follow-up

ETHIC-HF: Early Therapy with Ivabradine

in patients with Congestive Acute Heart
•Hidalgo FJ, et al. Int J Clin Cardiol. 2017;4:093. doi.org/10.23937/2378-2951/1410093.
Failure; bpm: Beats per min.
 Elevated Heart rate and high blood pressure
Among Normal Individuals

Associated with High Associated with

blood pressure and
increases the risk for increased peripheral
Hypertension resistance
Elevated Heart
Among hypertensive's
Rate
Increases the risk for
Increase in CV
cardiovascular
mortality
diseases

Pre-hypertensives with a heart rate ≥ 80 beats per minute were found to have a 50 % increase
in all-cause mortality
Proprietary and confidential — do not distribute
Reule S and Drawz PE. Curr Hypertens Rep. 2012 December ; 14(6): 478–484.
Thank You