Dr. Jervin Mano MD.,

Drugs for prophylaxis of

Myocardial Infarction

OVERVIEW

• Introduction

• Definition

• Epidemiology

• Drugs for primary prevention of MI

• Drugs for secondary prevention of MI

• Cardiac rehabilitation

• Recent advances

• Summary

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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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)

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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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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LARGEST SHARE IN NONCOMMUNICABLEDISEASES

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RISING PREVALENCE AND MORTALITY3

Forecasting the prevalence rate (%) of coronary heart disease (CHD) in India

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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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DRUGS FOR PRIMARY PREVENTION OF MI

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.

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

• 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.

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.

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.

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.

WHO RISK PREDICTION CHART

WHO RISK PREDICTION CHART

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

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.

DRUGS FOR SMOKING CESSATION

• Nicotine replacement therapy

• Bupropion

• Varenicline

DRUGS FOR SECONDARY PREVENTION OF MI

• 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 reductaseinhibitors

• Misc

CLASSIFICATION

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

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

ASPIRIN

• Antiplatelet drug

• MOA:

ASPIRIN

• Evidence : Antiplatelet Trialists’ Collaboration

• Dosage : post MI – 75-150mg/day

• ADR :

• GI symptoms

• Tinnitus

• Reye’s syndrome

• Toxicity

ASPIRIN

• Resistance :

• 25% population

• Due to non compliance, PD,PK , biochemical factors

• Aspirin resistant group has 4 times greater risk for recurrent infarction

CLOPIDOGREL

• 2nd generation thienopyridine

• Prodrug – requires activation

• MOA : irreversible inhibitor of platelet – P2Y12 receptors

• Dosage : 75mg/day

• Evidence :

• CURE

• CHARISMA

• COMMIT/CCS-2

• CAPRIE

CLOPIDOGREL

• Resistance :

• Genetic polymorphisms in the CYPs involved in the metabolic activation of clopidogrel. –CYP2C19

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

PRASUGREL

• Dosage : loading – 60mg , maintenance – 10mg

• ADR : increased risk of bleeding , not used in Cerebrovascular diseases

• Evidence : TRITON-TMI 38

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

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

• Indications:

• Atrial fibrillation

• LV thrombus, aneurysm

• Severe dilated LV

• History of thrombo-embolism

• ADR :

• Haemorrhage

• Teratogenic

• Transient alopecia

• Dermatitis, diarrhoea

• β receptor antagonist

• Cardioprotective effect by

• Antihypertensive effect –inhibiting vascular Adrreceptors, ↓ Renin Angiotensin production

• ↓ Myocardial demand & Cardiac contractility

• ↓ HR -> ↑ diastolic coronary perfusion

• Antiarrythymic property →Improve left ventricular structure and function

β- BLOCKERS

β- BLOCKERS

• Evidence :

• Norwegian Multicenter study- Timolol

• B-hat – Propranolol

• CAPRICON- CArvedilol Post infaRct survival COntRoling LV dysfunctioN

• COMMIT/CCS-2

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

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

CALCIUM CHANNEL BLOCKERS

• Guidelines :

• SIGN – only for hypertension post MI

• NICE- Normal ventricular function & when beta blockers are contraindicated

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

• ADR : Dry cough , angioedema, hyperkalemia

• Precautions :

• Aortic stenosis

• severe b/l renal artery stenosis

• Renal disease

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

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

• ADR : elevated liver enzymes , myopathy

• Precautions : patients with liver disease , high alcohol intake

• Alternate lipid lowering agents

• Fibrates

• Nicotinic acid

• Ezetimibe

NITRATES

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

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 .

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

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)

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.

PATIENTS WITH POST MI ARRYTHYMIAS

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

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

PATIENTS WITH PRIOR MYOCARDIAL INFARCTION WHO HAVE DIABETES

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)

PATIENTS WITH PRIOR MI AND HEART FAILURE

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

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.

EPLERENONE

• Potassium sparing diuretic

• MOA: aldosterone antagonist - selective for mineralocorticoid receptor

• Indication : heart failure & LV dysfunction post MI

• ADR : hyperkalemia, hypotension

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”.

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

RECENT ADVANCES

• ARBs

• Azilsartan - app

• Tasosartan - pIII

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

• ???

RECENT ADVANCES

• Squalene synthase inhibitors

• Apo A-1 Milano

• AGI- 1067

• Monoclonal antibodies

• Alirocumab

• AMG-145 – pIII

• Darapladib - pIII

• Inhibits lipoprotein associated phospholipase A2

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

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

SUMMARY

• Primary prevention

• Lifestyle modification – a important stay of Rx

• Secondary prophylaxis

• Future

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.