Drugs for prophylaxis of Myocardial Infarction Myocardial Infarction Drugs for primary prevention of MI Drugs for secondary prevention of MI Recent advances Cardiac rehabilitation

1. Dr. Jervin Mano MD.,
Drugs for prophylaxis of
Myocardial Infarction

2. OVERVIEW
• Introduction
• Definition
• Epidemiology
• Drugs for primary prevention of MI
• Drugs for secondary prevention of MI
• Cardiac rehabilitation
• Recent advances
• Summary

3. DEFINITION
• Coronary heart disease(CHD) is defined as myocardial
impairment due to imbalance between coronary blood
flow & myocardial requirement caused by change in
coronary circulation .
• Acute coronary syndrome encompasses both unstable
angina & MI
• Myocardial infarction is defined as irreversible
necrosis of myocardium secondary to prolonged
ischemia.
• Types : NSTEMI , STEMI
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4. CLINICAL CLASSIFICATION OF MI
• Type 1: Spontaneous myocardial infarction
• Type 2: Myocardial infarction secondary to an ischemic
imbalance
• Type 3: Myocardial infarction resulting in death when
biomarker values are unavailable
• Type 4a: Myocardial infarction related to percutaneous
coronary intervention (PCI)
• Type 4b: Myocardial infarction related to stent thrombosis
• Type 5: Myocardial infarction related to coronary artery
bypass grafting (CABG)

5. EPIDEMIOLOGY
• World :-
• Common in developed countries
• On the rise in developing countries
• 7.2 million deaths
• 12.2% of total deaths
• Highest coronary mortality rate – European region ,
SEAR .
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6. INDIA
• Will become the most important cause of death by 2015
• Cases of CHD may increase from about 2.9 crore in 2000
to as many as 6.4 crore in 2015
• Prevalence – urban: 6.4%, rural: 2.5%
• 25.1% of all deaths are due to CAD in urban area
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7. LARGEST SHARE IN NONCOMMUNICABLE
DISEASES
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8. RISING PREVALENCE AND MORTALITY3
Forecasting the prevalence rate (%) of coronary heart disease (CHD) in India
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10. WHAT INCREASES RISK?
You can’t help it!
• Age:
Men > 45;
Women > 55
• Sex
• Race
• Family History
• Personality
You can !!
• ↑ S.Cholesterol
• Smoking
• Hypertension
• Diabetes
• Obesity
• Alcohol
• Physical Inactivity
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11. DRUGS FOR PRIMARY PREVENTION
OF MI

13. ASPIRIN
• The results of the randomized trials indicated that, compared with placebo,
aspirin was associated with a 32% reduction in myocardial infarction
• A meta-analysis by the Antiplatelet Trialists Collaboration demonstrated
that, at low CVD risk, the benefits of aspirin are matched by the risks of
major bleeding and haemorrhagic stroke, and therefore aspirin is not
indicated
• When considering the use of aspirin, the benefits must be weighed against
the possible risks associated with its use
• If there are no contraindications (allergy or history of gastrointestinal
haemorrhage), low-dose aspirin (75 mg/day) is recommended for all
patients at high risk of developing CVD (≥20% over 10 years), provided the
blood pressure is controlled to <150/90 mmHg.

14. STATINS
• In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
(322), statins reduced the risk of non-fatal MI and fatal coronary
heart disease by 36% compared with placebo (P = 0.0005), in
patients with hypertension and at least three other
cardiovascular risk factors
• The Prospective Study of Pravastatin in the Elderly at Risk
(PROSPER) trial a lower risk of coronary death and non-fatal
myocardial infarction
• The results of the Cholesterol Treatment Trialists Collaboration
(332), based on 90 056 patients in 14 randomized trials, showed
that statin therapy can reduce the 5-year incidence of coronary
events, coronary revascularization by about one-fifth for each
mmol-per-litre reduction in LDL-cholesterol

15. • Meta-analysis of data from statin trials has not shown an excess
of adverse symptoms, including muscle pain and various
gastrointestinal symptoms, in the treated group. The absolute
risks of rhabdomyolysis and liver failure from hepatitis were low.
• Statins are recommended in patients with persistently high
serum cholesterol (> 5.0 mmol/l) at high risk of developing CVD
(≥20% over 10 years)
• The evidence for efficacy of other lipid-lowering agents in
primary prevention is weak.
• The Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) study.At 5 years follow-up, fenofibrate did not
significantly reduce the risk of coronary events.

16. ANTI HYPERTENSIVES
• The ALLHAT trial (288) compared the effects of a calcium-
channel blocker or an angiotensin- converting enzyme inhibitor
and a diuretic on the incidence of coronary heart disease and
other cardiovascular disease events.
• In the absence of any compelling indication, and of major
adverse effects , currently available evidence from comparative
trials of effi cacy and cardiovascular outcomes supports the use
of any one of the following classes of drugs as initial therapy:
ACE inhibitor, calcium-channel blocker, or low-dose diuretic.

17. FIXED DRUG COMBINATION(POLYPILL)
• As many high-risk patients would
benefit from treatment with several
drugs proven to reduce cardiovascular
disease, the notion of a combination
pill, using fixed dose formulations of
effective drugs has been proposed
• Benefits :- simplify selection of drugs
and ensure predefined doses.
• Defects:-overtreating people who are at
low cardiovascular risk and
undertreating people at substantial
risk.

18. HORMONE REPLACEMENT
• hormone therapy had been proposed for prevention of
cardiovascular disease in women
• This practice has been called into question following
publication of the results of several randomized clinical
trials, which showed no coronary protection, and the
Women’s Health Initiative, which indicated that long-term
use of oestrogen plus progestin was associated with
increased risks of cancer and cardiovascular disease.

19. WHO RISK PREDICTION CHART

20. WHO RISK PREDICTION CHART

21. 10-YEAR RISK OF CARDIOVASCULAR
EVENT > 30%
• Antiplatelet
• Low dose aspirin 75- 150 mg
• Lipid lowering
• Serum cholesterol should be reduced to less than 5.0 mmol/l
(LDL-cholesterol to below 3.0 mmol/l), or by 25%
• Statin is the preferred drug
• Anti hypertensives
• If persistent blood pressure ≥130/80 mmHg
• A low-dose thiazide like diuretic, ACE inhibitor, or calcium
channel blocker

22. 10-YEAR RISK OF CARDIOVASCULAR
EVENT 20–30%
• Antiplatelet
• Aspirin not recommended as risk outweighs benefit
• Lipid lowering drugs
• If >40 years with persistently high serum cholesterol (> 5.0
mmol/l), and or LDL-cholesterol > 3.0 mmol/l, despite a lipid-
lowering diet
• Statins preferred
• Anti hypertensive
• If persistent blood pressure ≥140/90 mmHge despite life style
strategies with professional assistance within 4–6 months
• A low-dose thiazide- like diuretic, ACE inhibitor, or calcium-
channel blocker is recommended as first line therapy.

23. DRUGS FOR SMOKING CESSATION
• Nicotine replacement therapy
• Bupropion
• Varenicline

24. DRUGS FOR SECONDARY PREVENTION
OF MI

25. • Antiplatelets
• Aspirin
• Clopidogrel
• Prasugrel
• Ticagrelor
• Anticoagulants
• Warfarin
• Rate limiting agents
• β blockers
• Ca2+ channel blockers
• Inhibition of Renin-
Angiotensin-Aldosterone axis
• ACE inhibitors
• ARBs
• Aldosterone antagonists
• Lipid management
• HMG CoA reductase
inhibitors
• Misc
CLASSIFICATION

26. MECHANISM OF ANTI-PLATELET
ACTIVITY
• Class I - ASA, NSAIDs & sulfinpyrazone
• block CO (cyclo-oxygenase)
• Class II - Dypyridamole
• inhibits phosphodiesterase-mediated breakdown of cyclic AMP
• prevents platelet aggregation
• Class III - Thienopyridines
• block binding of ADP to platelet receptor P2Y12 therby inhibiting
adenylyl cyclase
• Class IV - antibody, peptide & small molecule IIb/IIIA
receptor inhibitors

27. ASPIRIN
• Acetylsalicylic acid
• NSAID - Analgesic , antipyretic, anti
inflammatory, antiplatelet.
• One of the most widely used medications –
40,000 tones/ yr
• Largest body of evidence of any drug used in
secondary prophylaxis of MI

28. ASPIRIN
• Antiplatelet drug
• MOA:

29. ASPIRIN
• Evidence : Antiplatelet Trialists’ Collaboration
• Dosage : post MI – 75-150mg/day
• ADR :
• GI symptoms
• Tinnitus
• Reye’s syndrome
• Toxicity

30. ASPIRIN
• Resistance :
• 25% population
• Due to non compliance, PD,PK ,
biochemical factors
• Aspirin resistant group has 4
times greater risk for recurrent
infarction

31. CLOPIDOGREL
• 2nd generation thienopyridine
• Prodrug – requires activation
• MOA : irreversible inhibitor of platelet – P2Y12 receptors
• Dosage : 75mg/day
• Evidence :
• CURE
• CHARISMA
• COMMIT/CCS-2
• CAPRIE

32. CLOPIDOGREL
• Resistance :
• Genetic polymorphisms in the
CYPs involved in the metabolic
activation of clopidogrel. –
CYP2C19

33. PRASUGREL
• 3rd generation thienopyridine
• Advantages over clopidogrel
• All the absorbed drug is activated
• Onset of action is rapid
• Greater & predictable action
• CYP2C19 polymorphisms doesn’t affect much
• MOA : irreversible inhibitor of platelet – P2Y12
receptors

34. PRASUGREL
• Dosage : loading – 60mg , maintenance – 10mg
• ADR : increased risk of bleeding , not used in
Cerebrovascular diseases
• Evidence : TRITON-TMI 38

35. TICAGRELOR
• MOA : reversible oral P2Y12 receptor inhibitors
• Twice daily dosing necessary
• Evidence : PLATO – mortality was less in patients
randomised to ticagrelor,
• Significant reduction in stent thrombosis, MI & death from
any cause
• ADR :
• Bleeding , Dyspnoea
• Adverse cardiac & pulmonary function
• Bradycardia
• Increased conc.of uric acid & creatinine

36. ANTICOAGULANTS- WARFARIN
• MOA : inhibits vitamin K-reductase-> inhibit synthesis of
Factors II, VII, IX & X
• Evidence :
• WARIS
• ASPECT
• CARS
• Trials examining the use of warfarin post-MI have yielded
inconsistent results but most studies report an excess of
haemorrhagic complications

37. • Indications:
• Atrial fibrillation
• LV thrombus, aneurysm
• Severe dilated LV
• History of thrombo-embolism
• ADR :
• Haemorrhage
• Teratogenic
• Transient alopecia
• Dermatitis, diarrhoea

38. • β receptor antagonist
• Cardioprotective effect by
• Antihypertensive effect –
inhibiting vascular Adr
receptors, ↓ Renin
Angiotensin production
• ↓ Myocardial demand &
Cardiac contractility
• ↓ HR -> ↑ diastolic coronary
perfusion
• Antiarrythymic property →
Improve left ventricular
structure and function
β- BLOCKERS

39. β- BLOCKERS
• Evidence :
• Norwegian Multicenter study- Timolol
• B-hat – Propranolol
• CAPRICON- CArvedilol Post infaRct survival COntRoling LV
dysfunctioN
• COMMIT/CCS-2

41. β- BLOCKERS
• Drugs : Carvedilol, Metoprolol, Bisoprolol
• Guidelines : SIGN & NICE – start early as possible , lifelong
• ADR:
• Fatigue
• Can exacerbate Raynaud’s phenomenon, severe peripheral
vascular disease
• Bradycardia
• AV-block
• Precautions – Asthma, COPD, DM

42. CALCIUM CHANNEL BLOCKERS
• Indication : Normal ventricular function & when beta
blockers are contraindicated
• Drugs : verapamil , diltiazem
• MOA: Ca2+ channel blockade
• ADR:
• Constipation
• Bradycardia
• Accentuate conduction deficits

43. CALCIUM CHANNEL BLOCKERS
• Guidelines :
• SIGN – only for hypertension post MI
• NICE- Normal ventricular function & when beta
blockers are contraindicated

44. ACE - INHIBITORS
• MOA: ↓ cardiac preload, after load without causing reflex
tachycardia
• positive effects on post infarct remodelling & endothelial
function
• block local mediators of thrombosis.
• Evidence : HOPE trial
• Guidelines : SIGN – Unless CI long term Rx is
recommended in post MI with or without LV dysfunction

46. • ADR : Dry cough , angioedema, hyperkalemia
• Precautions :
• Aortic stenosis
• severe b/l renal artery stenosis
• Renal disease

47. ARBS
• MOA : blocks the AT II receptors
• Evidence : VALIANT study – non inferiority of the ARB
valsartan when compared head-to-head with an ACE
inhibitor
• Guidelines : ARBs are prescribed only when ACE inhibitors
are contraindicated
• ADR : Hypotension, hyperkalemia, teratogenic

48. LIPID MANAGEMENT- STATINS
• MOA: Inhibition of HMG-CoA reductase -> ↓ Cholesterol
synthesis, enhances elimination of LDL cholesterol
• Additional cardio protective anti inflammatory activity
• Evidence : Heart protection study : ↓ rate of vascular deaths,
major vascular events in high risk patients
• Guidelines : SIGN & NICE : statin therapy for all post MI
patients

49. • ADR : elevated liver enzymes , myopathy
• Precautions : patients with liver disease , high alcohol
intake
• Alternate lipid lowering agents
• Fibrates
• Nicotinic acid
• Ezetimibe

50. NITRATES
• Only used in acute MI to relieve cardiac pain due to
continuing myocardial ischemia .

51. HORMONE REPLACEMENT THERAPY
• Earlier Observational studies showed post menopausal
women on HRT have 40-50% lower incidence of
cardiovascular events
• HERS – no significant difference
• Increased risk for Ca. Breast .

52. WHEN TO START DRUG TREATMENT
Beta-blockers, Antiplatelet drugs (aspirin) and ACE
inhibitors
• should be initiated whilst patients are in hospital as there
is evidence to support benefit following early initiation.
• If this does not happen then primary care clinicians
should initiate them as soon after discharge as possible

53. WHEN TO START DRUG TREATMENT
• Although there is no evidence of the long-term benefit
from the use of statins initiated prior to 12 weeks post-
infarct, many patients will have been taking statins prior to
admission or will have them initiated in hospital.
• All patients discharged from hospital who are not already
taking a statin should be assessed and have treatment
initiated 12 weeks after a myocardial infarction (A)

54. CONTINUATION OF TREATMENT
• The treatment durations, for which there is at least
one trial that provides direct support, are
• three and a half years for antiplatelet drugs (aspirin)
• four years for beta-blockers and ACE inhibitors and
• six years for statins.
• In the absence of a clear reason to stop treatment it
seems reasonable to continue treatment indefinitely.

55. PATIENTS WITH POST MI
ARRYTHYMIAS

56. AMIODARONE
• 4-18% of patients with a/c MI go for fatal VF in 24-48 hrs
• 75% of sudden death deaths due to MI is due to ventricular
tachycardia/fibrillation
• MOA:
• Class III Antiarrhythmic
• Mild beta blocking, Ca blocking activity
• Na2+ channel blocking activity
• Dosage : 100mg/day – AF ; 300mg/day- VT,VF

57. AMIODARONE
• Evidence : CAMIAT, EMIAT
• Guidelines : SIGN - Patients with documented ventricular
arrhythmias
• ADR :
• Heart block – in pre existing SA, AV node disease
• Pulmonary disease
• Hepatitis
• Photodermatitis
• Corneal microdeposits
• Thyroid disorders
• Increased LDL levels

58. PATIENTS WITH PRIOR
MYOCARDIAL INFARCTION WHO
HAVE DIABETES

59. INSULIN OR OHA
• There is evidence that intensive insulin therapy initiated
soon after admission for acute myocardial infarction
reduces mortality.
• Mellbin et al.- insulin Rx is inferior to Oral hypoglycemic
drugs (DIGAMI II)

60. PATIENTS WITH PRIOR MI
AND HEART FAILURE

61. LONG TERM TREATMENT
All patients should be offered long term treatment with
• an ACE inhibitor and
• then a Beta-blocker (not all beta-blockers have a
licence for this indication).
• In addition they should be treated with an
antiplatelet drug (aspirin).
• Patients who have moderate or severe heart failure
(New York Heart Association (NYHA) grade 3 or 4)
should be treated with Spironolactone.
• All of these treatments are cost effective

62. CONTINUATION OF TREATMENT
• Based on the evidence from the trials, treatment
should continue long term. The treatment durations,
for which there is at least one trial that provides direct
support,
• are 3 ½ yrs for ACE inhibitors
• 2 ½ years for Beta-blockers
• 2 years for Spironolactone
• In the absence of a clear reason to stop treatment it
seems reasonable to continue treatment indefinitely.

63. EPLERENONE
• Potassium sparing diuretic
• MOA: aldosterone antagonist - selective for
mineralocorticoid receptor
• Indication : heart failure & LV dysfunction post MI
• ADR : hyperkalemia, hypotension

64. CARDIAC REHABILITATION PROGRAMS
© CONTINUING MEDICAL IMPLEMENTATION
…...BRIDGING THE CARE GAP
• Definition
• “the enhancement and maintenance of cardiovascular
health through individualized programs designed to
optimize physical, psychological, social, vocational and
emotional status”.
• May include multifactorial secondary prevention
• defined as “the sum total of all interventions, both
physiological and behavioral, designed to favorably
modify an individual’s lifestyle, and enhance adherence
and compliance with long-term behaviors compatible
with minimizing disease progression”.

65. RECENT ADVANCES
• Newer antiplatelets –
• Ticagrelor
• Terutroban – pIII – thrombaxane Rs antagonist
• Thrombin Rs antagonist
• Vorapaxar – waiting for approval
• Protease activating Rs-1 antagonist
• ACE inhibitors
• Alacepril
• Movetipril

66. RECENT ADVANCES
• ARBs
• Azilsartan - app
• Tasosartan - pIII

67. RECENT ADVANCES
Hypolipidemic agents
• CETP inhibitors
• MOA - inhibit cholesterylester transfer protein (CETP), which
facilates transfer of cholesteryl esters from HDL to VLDL or
LDL
• Anacetrapib- pIII
• Evacetrapib- pIII
• Torcetrapib- excess deaths in phase III.
• Dalcetrapib – failed – no meaningful efficacy
• ???

68. RECENT ADVANCES
• Squalene synthase inhibitors
• Apo A-1 Milano
• AGI- 1067
• Monoclonal antibodies
• Alirocumab
• AMG-145 – pIII
• Darapladib - pIII
• Inhibits lipoprotein associated phospholipase A2

69. NEWER THERAPIES
• Stem cell treatment :
• Coronary artery injections of
stem cells derived from their
own bone marrow after a
myocardial infarction show
improvements in left
ventricular ejection fraction
and end-diastolic volume .
• Clinical trials of progenitor cell
infusion as a treatment approach
to ST elevation MI are
proceeding

70. NEWER THERAPIES
• Biomaterial and tissue engineering
1. Polymeric left ventricular restraints in the
prevention of heart failure
2. in vitro engineered cardiac tissue, which is
subsequently implanted in vivo.
3. Injecting cells and/or a scaffold into the
myocardium to create in situ engineered cardiac
tissue

71. SUMMARY
• Primary prevention
• Lifestyle modification – a important stay of Rx
• Secondary prophylaxis
• Future

72. REFERENCE
• Harrison’s principles of internal medicine , 18th edition
• Goodman and Gilman's the pharmacological basis of therapeutics 12th
edition
• Basic & Clinical pharmacology , 12th Ed., Betram g. Katzung
• Oxford textbook of medicine 4th edition
• Principles of Pharmacology 2nd edition, HL Sharma KK Sharma
• Lang, Ninian, and Keith Fox. "Current drug therapies for the secondary
prevention of MI." Prescriber 19.1 (2008): 14-25.
• Sign guidelines no 41
• Matzke, Gary R., Barbara G. Wells, and L. Michael Posey,
eds.Pharmacotherapy: a pathophysiologic approach. New York, NY: McGraw-
Hill, 2005.