AND SECONDARY
PREVENTIONS OF
CARDIOVASCULAR
MORBIDITY AND
MORTALITY
1
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core ...
CVDS: CURRENT GLOBAL
BURDEN
2
3
CVD RISK FACTORS
 Cardiovascular risk factors 
 Non-modifiable: Family history, ethnicity and age
 Modifiable: Hyperten...
WHAT ARE CVDS?
 Cardiovascular diseases (CVDs) are a group of disorders of
the heart and blood vessels and they include:
...
COMMON SYMPTOMS OF
CVDS
 Symptoms of heart attacks and strokes
 Pain or discomfort in the centre of the chest
 Pain or ...
PRIMARY PREVENTION OF
CVDS
 Population level primary prevention:
 Lowering the average risk factors like BP, LDL cholest...
PRIMARY PREVENTION OF
CVDS
8
• Statin: simvastatin
• CCB: amlodipine
low dose
• ARB: losartan
low dose
• Thiazide:
hydroch...
PRIMARY PREVENTION:
POLYPILL EFFICACY
9
Wald N. (2014). FDA Presentation
SECONDARY PREVENTION OF
CVDS
 For secondary prevention of CVDs in those with established disease,
including diabetes, tre...
5-COMPONENT POLYPILL
EFFICACY FOR SECONDARY
PREVENTION
11
Wald NJ, Law MR. (2003) BMJ 326:1419-24
THE CADILA POLYCAPTM
USED IN
TIPS1 & PK STUDY
 Hydrochlorothiazide (12.5mg)
 Atenolol (50mg)
 Ramipril (5mg)
 Simvasta...
Reduction in
Heart Rate
Polycap -7.0
Other Atenolol
arms
-7.0
Non Atenolol arms 0.0
1)
POLYCAP: MEAN CHANGES IN BP, HEART
...
• Both groups showed
reduction in LDL levels
• Similar reduction in 11-
dehydrothromboxane B2
• Polycap conserved the LDL
...
 518 patients with previous vascular
disease or DM
 Assigned to a single (regular dose) or
to 2 capsules of the Polycap ...
 Potential reduction in CVD
attacks
 An apt therapeutic option for
 High risk CVD patients
 Secondary prevention
 Eas...
ARE THE EFFECTS INDEPENDENT
IN REDUCING RISK?
 YES
 Evidence
 the mechanisms are different
 cohort studies
 randomise...
THE PHARMACOKINETIC (PK)
ISSUES WITH POLYCAP
 While the efficacy of giving multiple proven drugs in a
single pill or caps...
A five arm
randomized,
single-dose,
two-period,
two-treatment,
two-sequence,
crossover trial
in a total of
195 healthy
hum...
Ramipril
Ramiprilat
Aspirin
Atenolol
Hydrochlorthiazide
Simvastatin20
PatelA.,ShahT.,….ChakrabortyB.S.(2010).AmJCardiovasc...
CONCLUSIONS OF THE
POLYCAPTM
PK STUDY
 Aspirin, ramipril, atenolol, and hydrochlorothiazide
from Polycap were absorbed wi...
FINAL REMARKS
22
 Polycap provides potential primary reduction in CVD
attacks
 An apt therapeutic option for
 High risk...
THANK YOU VERY
MUCH
23
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Polypill for primary and secondary preventions of cardiovascular

A fixed dose combination for CVDs
Published on: Mar 4, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Polypill for primary and secondary preventions of cardiovascular

  • 1. AND SECONDARY PREVENTIONS OF CARDIOVASCULAR MORBIDITY AND MORTALITY 1 Dr. Bhaswat S. Chakraborty Sr. VP & Chair, R&D Core Committee Cadila Pharmaceuticals Ltd. Presented at the IACS Conference 'Translational Research in Cardiovascular Sciences” Anand, Gujarat, February 5-6, 2016
  • 2. CVDS: CURRENT GLOBAL BURDEN 2
  • 3. 3
  • 4. CVD RISK FACTORS  Cardiovascular risk factors   Non-modifiable: Family history, ethnicity and age  Modifiable: Hypertension, high cholesterol, obesity, physical inactivity, diabetes, unhealthy diets, tobacco, and harmful use of alcohol  Modifiable risk factors  Hypertension – biggest risk factor for stroke; significant role in heart attacks; preventable & treatable  Physical inactivity & obesity increases heart disease and stroke risk by 50%.   Type2 diabetes doubles coronary heart disease and stroke risk  A diet high in saturated fat increases the risk of heart disease and stroke  Chronically stressful life, social isolation, anxiety and depression  Up to 1 or 2 alcohol drinks OK but above this will damage the heart muscle  Certain medicines e.g., contraceptive pill and hormone replacement therapy (HRT).  Left ventricular hypertrophy (LVH) 4
  • 5. WHAT ARE CVDS?  Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels and they include:  Coronary heart disease – disease of the blood vessels supplying the heart muscle  Cerebrovascular disease – disease of the blood vessels supplying the brain  Peripheral arterial disease – disease of blood vessels supplying the arms and legs  Rheumatic heart disease – damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal bacteria;  Congenital heart disease – malformations of heart structure existing at birth  Deep vein thrombosis and pulmonary embolism – blood clots in the leg veins, which can dislodge and move to the heart and lungs 5
  • 6. COMMON SYMPTOMS OF CVDS  Symptoms of heart attacks and strokes  Pain or discomfort in the centre of the chest  Pain or discomfort in the arms, the left shoulder, elbows, jaw, or back  Difficulty or shortness of breath; feeling sick or vomiting; feeling light- headed or faint; breaking into a cold sweat; and becoming pale  Women are more likely to have the above  Symptoms of stroke  Sudden weakness of the face, arm, or leg, most often on one side of the body  Numbness of the face, arm, or leg, especially on one side of the body  Confusion, difficulty speaking or understanding speech  Difficulty seeing with one or both eyes  Difficulty walking, dizziness, loss of balance or coordination  Severe headache with no known cause  Fainting or unconsciousness 6
  • 7. PRIMARY PREVENTION OF CVDS  Population level primary prevention:  Lowering the average risk factors like BP, LDL cholesterol, smoking and obesity in the entire population  Examples of population-wide interventions  comprehensive tobacco control policies  taxation to reduce the intake of foods that are high in fat, sugar and salt  building walking and cycle paths to increase physical activity  strategies to reduce harmful use of alcohol  providing healthy school meals to children.  Individual level 1o prevention:  targeted those at high total cardiovascular risk or  those with single risk factor levels above traditional thresholds, e.g., hypertension and hypercholesterolemia 7
  • 8. PRIMARY PREVENTION OF CVDS 8 • Statin: simvastatin • CCB: amlodipine low dose • ARB: losartan low dose • Thiazide: hydrochlorothiazide low dose • No Aspirin Wald NJ, Morris JK. Eur J Epidemiol 2014. DOI 10.1007/s10654-014-9932-1 Age of starting preventive treatment: 50 years Among these, % who benefit: 33% Their average benefit: 8 years (Years of life gained without an IHD event or stroke.)
  • 9. PRIMARY PREVENTION: POLYPILL EFFICACY 9 Wald N. (2014). FDA Presentation
  • 10. SECONDARY PREVENTION OF CVDS  For secondary prevention of CVDs in those with established disease, including diabetes, treatment with the following medications are necessary:  Aspirin, beta-blockers, ACE inhibitors & statins 10 Yusuf S. (2002). THE LANCET , 360: 2-3
  • 11. 5-COMPONENT POLYPILL EFFICACY FOR SECONDARY PREVENTION 11 Wald NJ, Law MR. (2003) BMJ 326:1419-24
  • 12. THE CADILA POLYCAPTM USED IN TIPS1 & PK STUDY  Hydrochlorothiazide (12.5mg)  Atenolol (50mg)  Ramipril (5mg)  Simvastatin (20mg)  Acetyl Salicylic Acid (ASA)  (100mg, Enteric Coated)  In a 00 hard gelatin capsule 12
  • 13. Reduction in Heart Rate Polycap -7.0 Other Atenolol arms -7.0 Non Atenolol arms 0.0 1) POLYCAP: MEAN CHANGES IN BP, HEART RATE Lancet. 2009 Apr 18;373(9672):1341-51 Polycap reduces BP and Heart Rate similar to component drugs 13
  • 14. • Both groups showed reduction in LDL levels • Similar reduction in 11- dehydrothromboxane B2 • Polycap conserved the LDL reduction and Antiplatelet activity TIPS1: MEAN CHANGES IN LDL & PLATELET FUNCTION WITH POLYCAPTM Polycap reduces Lipids and platelet activity similar to component drugs 14 LDL11-dehydrothromboxaneB2 14
  • 15.  518 patients with previous vascular disease or DM  Assigned to a single (regular dose) or to 2 capsules of the Polycap (full dose)  Full dose showed superior reduction in  BP  LDL, compared to regular dose  Similar tolerability profile in both arms THE INDIAN POLYCAP STUDY 2 (TIPS 2) POLYCAPTM : MEAN CHANGES IN BP Circ Cardiovasc Qual Outcomes. 2012 Jul 1;5(4):463-71 Polycap can be titrated from regular to full dose for better control LipidloweringBPlowering 15
  • 16.  Potential reduction in CVD attacks  An apt therapeutic option for  High risk CVD patients  Secondary prevention  Easy Dosing  Once daily dosing improves patient compliance  Easy to titrate  Start with 1 cap OD, move to 2 caps/day if needed THE EVIDENCE OF POLYCAP’S EFFECTIVENESS Circ Cardiovasc Qual Outcomes. 2012 Jul 1;5(4):463-71 TIPS 1 and TIPS 2: Result Summary TIPS 1 (Regular Polycap) TIPS 2 (Full dose Polycap) 16
  • 17. ARE THE EFFECTS INDEPENDENT IN REDUCING RISK?  YES  Evidence  the mechanisms are different  cohort studies  randomised trials  e.g. Heart Protection Study, 2002; EUROPA trial, 2002; TIPS (2009)  So, when used together in appropriate patients, up to 80% future CV events can be prevented  Potential benefits of quitting smoking, diabetes control and exercise can virtually eliminate the entire CVD risk in in high-risk individuals 17
  • 18. THE PHARMACOKINETIC (PK) ISSUES WITH POLYCAP  While the efficacy of giving multiple proven drugs in a single pill or capsule has been proven, the questions are:  Is such a combination of several active drugs safe and tolerable?  Is there any drug-drug and drug-metabolite interaction?  Such interactions can lead to toxic or suboptimal levels of one or more ingredients (and metabolites), which may lead to increased adverse effects or alternatively decreased efficacy  Is the bioavailability of some or all its components preserved or getting altered?  While TIPS1 and TIPS2 studied the efficacy of risk factor reductions and clinical safety, we also studied the PK and drug-drug interaction of Polycap 18 Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103
  • 19. A five arm randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial in a total of 195 healthy humans 19 Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103
  • 20. Ramipril Ramiprilat Aspirin Atenolol Hydrochlorthiazide Simvastatin20 PatelA.,ShahT.,….ChakrabortyB.S.(2010).AmJCardiovascDrugs,10:95-103
  • 21. CONCLUSIONS OF THE POLYCAPTM PK STUDY  Aspirin, ramipril, atenolol, and hydrochlorothiazide from Polycap were absorbed with a comparable rate and extent with those of single ingredient formulations  Preservation of bioavailabilty  There was no kinetic drug-drug interaction in vivo  For simvastatin, there was a loss of bioavailability (~20%) but >equal increase in bioavailability of simvastatin acid  The PK study of Polycap establishes the required bioavailability for all its component drugs, thus explaining its reported efficacy kinetically 21 Patel A., Shah T., ….Chakraborty B.S. (2010). Am J Cardiovasc Drugs, 10:95-103
  • 22. FINAL REMARKS 22  Polycap provides potential primary reduction in CVD attacks  An apt therapeutic option for  High risk CVD patients  Secondary prevention  Once daily dosing improves patient compliance  Easy to titrate  Start with 1 cap OD, move to 2 caps/day if needed  No loss of bioavailability of individual components when formulated as Polycap  No drug-drug or drug-metabolite interaction  Affordable in low income countries
  • 23. THANK YOU VERY MUCH 23

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