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The Double Edged Pill: Should Atorvastatin + Aspirin FDC be given to All?

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Deaths from cardiovascular disease (CVD): Global dataCardiovascular Diseases (CVDs). WHO Website. http://www.who.int/mediacentre/factsheets/fs317/en/index.html. Accessed April 29, 2013. 2012 European Cardiovascular Disease Statistics. European Society of Cardiology. http://www.escardio.org/about/what/advocacy/EuroHeart/Pages/2012-CVD-statistics.aspx. Accessed April 29, 2013. America's Heart Disease Burden. CDC Website. http://www.cdc.gov/heartdisease/facts.htm. Accessed April 29, 2013. Shou HS, Zhi KL, Lin GR. Outline of the Report on Cardiovascular Disease in China, 2010. Biomed Environ Sci. 2012; 25(3):251-256.Europe: 4 million deaths annuallyLow- and middle-income countries: Account for 80% of CVD deathsGlobal: 17.3 million deaths due to CVD385,000 people die annually due to CHD in the United States of America China: 3 million deaths annuallyCardiovascular disease (CVD) is the leading cause of death globally. According to World Health Organization (WHO), 17.3 million people died due to CVDs in 2008, constituting 30% of all deaths.1 Of these deaths, an estimated 7.3 million were due to coronary heart disease (CHD) and 6.2 million were due to stroke.1 The 2012 European Cardiovascular Disease Statistics reports that CVD causes 4 million deaths annually in Europe.2 According to the Center of Disease Control and Prevention (CDC), 385,000 people die annually due to CHD in the United states (US).3 Over 80% of CVD deaths occur in low- and middle-income countries.1 CVD causes 3 million deaths annually in China.4

References:Cardiovascular Diseases (CVDs). WHO Website. http://www.who.int/mediacentre/factsheets/fs317/en/index.html. Accessed April 29, 2013. 2012 European Cardiovascular Disease Statistics. European Society of Cardiology. http://www.escardio.org/about/what/advocacy/EuroHeart/Pages/2012-CVD-statistics.aspx. Accessed April 29, 2013. America's Heart Disease Burden. CDC Website. http://www.cdc.gov/heartdisease/facts.htm. Accessed April 29, 2013. Shou HS, Zhi KL, Lin GR. Outline of the Report on Cardiovascular Disease in China, 2010. Biomed Environ Sci. 2012; 25(3):251-256.2Prevalence of CVD: IndiaCVD is the largest cause of mortality in India1Approximately 2 million deaths annually1The CAD rates among Indians worldwide are 50% to 400% higher than people of other ethnic origins irrespective of gender, religion or social class2Indians have a high rate of premature CVD33.532.521.510.502010All ages< 50 yrs of age< 40 yrs of age< 30 yrs of ageDeath due to CAD20152.32.90.71.5}}}}0.920.30.4226%1.1432%31%27%1. Gupta R, Guptha S, Sharma KK, Gupta A, Deedwania P. Regional variations in cardiovascular risk factors in India: India heart watch. World J Cardiol. 2012;4(4):112-120.2. Enas EA, Senthilkumar A. Coronary artery disease in Asian Indians: an update and review. Internet J Cardiol. 2001;1(2). doi:10.5580/5ba.3. Enas EA, Yusuf S, Sharma S. Coronary artery disease in South Asians. Second meeting of the International Working Group. 16 March 1997, Anaheim, California. Indian Heart J. 1998;50(1):105-113.CVD is the largest cause of mortality in India, leading to approximately 2 million deaths annually.1 The CAD rates among Indians worldwide are 50% to 400% higher than people of other ethnic origins irrespective of gender, religion or social class.2 Indians have a high rate of premature CVD. Onset of first MI is 5 to 10 years earlier in Indians. The rate of MI and death among people aged 140/90 mm HgBeta-blockers, ACEI, thiazide diureticLipid-lowering drugsAll patients with established CHD and/or cerebrovascular diseaseTreatment with statins is recommended for all patients with established CHDTreatment with a statin should be considered for all patients with established CeVDOther lipid lowering agents are not recommended, either as an alternative to statins or in addition to themHypoglycaemic drugsMetformin and/or insulin as appropriateAntiplatelet drugsAspirin should be initiated early and continued lifelong in patients with established CHD, or history of TIA or strokeFollowing Myocardial Infarction (MI)ACE inhibitors are recommended in all patients following MIB-blockers in patients with history of MI and CHD who have developed major LV dysfunctionAnticoagulantsLong-term anticoagulation is recommended for patients with a history of stroke or TIA who are in atrial fibrillation, at low risk of bleedingCoronary revascularisationPatients at moderate and high risk who are likely to have left main stem or triple vessel diseaseCarotid endarterectomyPatients with a previous TIA or non-disabling stroke; severe ipsilateral carotid stenosis (70%99%) and patients with moderate degrees of stenosis (50%69%)CVD: Secondary preventionPrevention of Cardiovascular Disease. WHO Website. http://www.who.int/cardiovascular_diseases/guidelines/PocketGL.ENGLISH.AFR-D-E.rev1.pdf. Accessed April 30, 2013.Secondary prevention as recommended by the WHO guidelines includes lifestyle modification, antihypertensive drugs, lipid-lowering drugs and hypoglycaemic drugs. Treatment with statins is recommended in all patients with established CHD. Treatment should be continued for long-term, probably lifelong. Treatment with a statin should be considered in all patients with established CeVD, especially if they also have evidence of established CHD. Other lipid-lowering agents are not recommended, either as an alternative to statins or in addition to them. Aspirin should be initiated early and continued lifelong in patients with established CHD or history of TIA or stroke.

ACE inhibitors are recommended in all patients following myocardial infarction (MI). -blockers are recommended in patients with history of MI and CHD who have developed major left ventricular dysfunction.

Long-term anticoagulation is recommended in patients with history of stroke or TIA who are in atrial fibrillation, at low risk of bleeding.Coronary revascularisation is recommended in patients at moderate and high risk who are likely to have left main stem or triple-vessel disease.Carotid endarterectomy is recommended in patients with previous TIA or non-disabling stroke; severe ipsilateral carotid stenosis (70%99%) and in patients with moderate degrees of stenosis (50%69%).

Reference:Prevention of Cardiovascular Disease. WHO Website. http://www.who.int/cardiovascular_diseases/guidelines/PocketGL.ENGLISH.AFR-D-E.rev1.pdf. Accessed April 30, 2013.

6CVD: Primary preventionPrimary prevention: WHO guidelinesPrevention of Cardiovascular Disease. WHO Website. http://www.who.int/cardiovascular_diseases/guidelines/PocketGL.ENGLISH.AFR-D-E.rev1.pdf. Accessed April 30, 2013.Dietary changesReduce total fat (30% of calories) and saturated fat (10% of calories) intakeReplace with PUFA and MUFAReduce salt intake (108 mg/dL.

Reference:Prevention of Cardiovascular Disease. WHO Website. http://www.who.int/cardiovascular_diseases/guidelines/PocketGL.ENGLISH.AFR-D-E.rev1.pdf. Accessed April 30, 2013.

7Significance of primary prevention1Mohamad TN. Primary and Secondary Prevention of Coronary Artery Disease. Medscape Website. Available at http://emedicine.medscape.com/article/164214-overview#aw2aab6b3. Accessed on May 7, 2013Primary prevention include preventive measures in patients without diagnosed disease (does not have clinically manifest disease) reduces mortality and morbidity due to MI and heart failure, decreases the need for coronary revascularization procedures thereby reducing the cost associated with disease and extends and improves the quality of life.

Reference:

1. Mohamad TN. Primary and Secondary Prevention of Coronary Artery Disease. Medscape Website. Available at http://emedicine.medscape.com/article/164214-overview#aw2aab6b3. Accessed on May 7, 2013

8AssessmentDuring a routine check-up you detect a 50-year-old man to have high blood sugar (newly diagnosed diabetic) with no other risk factors present. Apart from OHG agents, what would you consider from a preventive viewpoint?a) Statin + Aspirinb) Aspirinc) Statin

A survey conducted in APICON 2013 alarmingly showed that 43% prescribers would give aspirin or statin and aspirin combination to this patient Is this right or wrong?During routine check up you detect a 50 year old man to have high blood sugar (newly diagnosed diabetic) with no other risk factors present. Apart from OHG agents, what would you consider from a Preventive viewpoint?

The options are combination of statin and Aspirin, monotherapy with aspirin or Statin.

9Increasing usage of Atorvastatin + Aspirin combination in India64% of prescribers use statin-aspirin combination for primary prevention1 [Survey of Indian Physicians]What is driving the increased use of this FDC?Benefit of Statin in Primary Prevention well recognisedIntent to provide Statin at Low Cost

1. Client Data on File.2. APICON Survey. Client Assets on File.Adverse effects of aspirin are less well recognised in primary prevention, leading to indiscriminate use Data show that 64% of prescribers use statin-aspirin combination for primary prevention of CVD.1 The APICON survey showed that more than 90% of the prescribers used combination of aspirin and statin in the patients with even mild CVD risk factors.2

Despite clinical study evidences proving benefits of statin for primary prevention, practitioners continue to advise combination therapy with the intention of providing primary prevention at a lesser cost. Adverse effects of aspirin are less well recognised in primary prevention, leading to indiscriminate use.

References: Client Data on File.2. Many Low/Intermediate-Risk Patients Still get Aspirin for Primary Prevention: PARADIGM. http://www.theheart.org/article/1299277.do. Accessed April 22, 2013.3. APICON Survey. Client Assets on File.

10Use of Aspirin: Prescription ScenarioA survey conducted with 60 renowned doctors, including general practitioners, physicians and diabetologists

APICON Survey. Client Assets on File.

Use of aspirin + statin for all patients for primary prevention of CVD can be considered as indiscriminate Results of APICON survey The APICON survey was conducted to analyse the use/prescription of aspirin in general practice. The survey included 60 renowned doctors, including general practitioners, physicians and diabetologists. Results revealed that 63% prescribers would give statin and aspirin combination to a 60-year-old hypertensive individual (with no other risk factors). In all, 43% prescribers would give aspirin or statin and aspirin combination to a 40-year-old newly diagnosed diabetic patient (with no other risk factors). Ten out of sixty responders said they would give atorvastatin and aspirin to all patients (from mild-risk to high-risk cases).

Reference: APICON Survey. Client Assets on File.

11End of the polypill in primary preventionPolypill was intended for use in both primary and secondary prevention:

Low-dose aspirin (50 to 125 mg/d) Folic acid 0.8 mg/dA potent statin (eg, atorvastatin 10 mg or simvastatin 40 to 80 mg)3 BP-lowering drugs at half the standard dose (among thiazide diuretics, beta-blockers, ACE inhibitors, ARBs, and calcium channel blockers)In the use of aspirin in a combination product for primary prevention, the benefits are lower than risks, and is not supported by guidelines21. Lonn E. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges and future directions. Circulation. 2010;122:2078-2088.2. Morant SV, et al. Cardiovascular prophylaxis with aspirin: costs of supply and management of upper gastrointestinal and renal toxicity. Br J Clin Pharmacol. 2003;57:188-198.

We took a decision to leave aspirin out of a CVD prevention polypill because it is the only component that runs a reasonable chance of serious harm

Dr David S Wald (Wolfson Institute of Preventive Medicine, London, UK)Potential advantages of polypillImproved adherenceReduced cost1Limitations of polypillAdverse effects2 of Aspirin such as GI ulcer and fatal bleeding eventsRef: http://www.theheart.org/article/1428261.do

The term polypill is a combination of multiple drugs used in both primary and secondary prevention. Wald and law proposed a polypill containing low-dose aspirin (50 to 125 mg/d); Folic acid 0.8 mg/d; a potent statin (eg, atorvastatin 10 mg or simvastatin 40 to 80 mg), and 3 BP-lowering drugs at half the standard dose (among thiazide diuretics, -blockers, ACE inhibitors, ARBs, and calcium channel blockers). The potential advantages of polypill include improved delivery of care, improved adherence and reduced cost. However such combination can reduce the cost but not the adverse effects of the drug especially aspirin. Hence use of aspirin in a combination product would not without the cost.

Reference:Lonn E. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges and future directions. Circulation. 2010; 122:2078-20882. Morant SV, et al. Cardiovascular prophylaxis with aspirin: costs of supply and management of upper gastrointestinal and renal toxicity. Br J Clin Pharmacol. 2003;57:188-198.

12Use of aspirin: What do the guidelines recommend?Primary preventionFDA has not approved the use of aspirin for primary prevention (diabetic and non-diabetic patients)1Its net benefits in these patients without previous CVD events is controversial2ESC does not recommend aspirin for primary prevention due to increased risk of major bleeding3 According to WHO, primary prevention and secondary prevention are defined as:Secondary preventionIt is effective as a secondary prevention in diabetic patients with previous history of MI or stroke2Pgnone M. Aspirin for primary prevention of cardiovascular events in people with diabetes. A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes care. 2010;33(6).ADA. Standards of Diabetes Care 2013. Diabetes care. 2013:36(supplement 1). doi: 10.2337/dc13-S011.Perk J, Backer JD, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33:1635-1701.Although aspirin is used in combination with atorvastatin, guidelines do not recommend aspirin for primary prevention in low-risk patients. FDA has not approved the use of aspirin for primary prevention (diabetic and non-diabetic patients).1 ESC does not recommend aspirin for primary prevention due to increased risk of major bleeding.2 Its net benefits in these patients without previous CVD events are controversial.3Aspirin is effective for secondary prevention in diabetic patients with previous history of MI or stroke.2

References:1. Pgnone M. Aspirin for primary prevention of cardiovascular events in people with diabetes. A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes care. 2010; 33(6).2. Perk J, Backer JD, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33:1635-17013. ADA. Standards of Diabetes Care 2013. Diabetes care. 2013:36(supplement 1). doi: 10.2337/dc13-S011..

13Use of aspirin in diabetic patients: RecommendationsAmerican Diabetes Association1,2

Diabetes is not to be treated as a CHD risk equivalent anymoreWas considered as CHD risk (ADA 2003)Not all diabetics need to be given aspirinLow-dose aspirin should be considered in diabetic patients at high CVD riskAspirin is not recommended in diabetic patients with low/intermediate CVD risk as the low benefit is outweighed by the risk of bleeding Aspirin is associated with 54% increased risk of GI bleeding when used for primary preventionStatins and other therapies should be considered to low the CVD event risk before considering aspirinStandards of Diabetes Care 2013. Diabetes Care. 36(supplement 1). Pgnone M. Aspirin for primary prevention of cardiovascular events in people with diabetes. A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes Care. 2010;33(6).The ADA 2010 updated that diabetes should not to be treated as a CHD risk equivalent anymore, as was previously considered. This implies that not all diabetics should be given aspirin. Low-dose aspirin should be considered in diabetic patients at high CVD risk. Aspirin is not recommended in diabetic patients with low CVD risk or intermediate CVD risk as the low benefit is outweighed by the risk of significant bleeding. The net benefit of aspirin in primary prevention for diabetic and non-diabetic patients without any previous CV event history is questionable.1

According to the ADA position statement, aspirin may cause major intra-cranial and extra-cranial bleeding events in diabetic and non-diabetic patients. Aspirin is also associated with 54% increased risk of GI bleeding when used for primary prevention.2

References:Standards of Diabetes Care 2013. Diabetes Care. 36(supplement 1). Pgnone M. Aspirin for primary prevention of cardiovascular events in people with diabetes. A position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes Care. 2010;33(6).

14Benefit of aspirin for primary prevention is relatively less in patients with or without diabetesDiabetic patients had a higher rate of bleeding55% increased bleeding risk among diabetic patients taking aspirin compared with non-diabetic patients2Aspirin increases major bleeding by 66% and gastrointestinal bleeding by 37% and haemorrhagic stroke by 36%21 to 2 major bleeding episodes/year in every 1000 patients treated with low-dose aspirin1

Aspirin Risk Vs. Benefit in DiabetesBerardis GD et al. Association of aspirin use with major bleeding in patients with or without diabetes. JAMA. 2012;307(21):2286-2294Raju NC, Eikelboom JW. The aspirin controversy in primary prevention. Curr Opin Cardiol 2012, 27:499507Patients with diabetes had a high rate of bleeding that was associated with aspirin use.1 DiabetesLong-rank P =.85 for aspirin use vs no aspirin use No diabetesLong-rank P1 other CVD risk factor(s)Age 1 other CVD risk factorsLDL-C >100 mg/dLStatinThe American Diabetes Association (AHA) guidelines also consider LDL-C as the primary target of therapy for dyslipidaemia management. LDL-targeted statin therapy is also the preferred mode of lipid management.1

The AHA guidelines published in 2005 specified the treatment strategies for managing diabetic dyslipidaemia as a part of metabolic syndrome. The primary target of the therapy still remains LDL-C. Secondary target of the therapy is non-HDL-C when TG level is >200 mg/dL. TG-lowering treatments should be considered if the level is >500 mg/dL. Increasing the HDL-C level is considered as a tertiary aim of the therapy. If secondary targets are not achieved with statin therapy, intensification of the statin therapy or addition of fibrates or niacin to the existing statin regimen should be considered.2 As per the ADA guidelines, any patient with type 2 diabetes who is >40 years of age or has LDL-C >100 mg/dL or has an additional CVD risk factor should be prescribed a statin.

References:Standards of Medical Care in Diabetes-2009. Diabetes Care. 2009;32(suppl 1):S13-S61.Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735-2752.54Chart10.290.3680.5670.650.8650.7920.5070.476

MaleFemalePrevalence (%)

Acr12FCityTownPeriurbanElevated total cholesterol24.915.49.7Elevated triglyceride30.128.121.7Low HDL27.431.541.1MaleFemaleElevated TC29.0%36.8%Raised LDL-C56.7%65.0%Low HDL-C86.5%79.2%Elevated TG50.7%47.6%

Acr12F

Elevated total cholesterolElevated triglycerideLow HDL

MaleFemalePrevalence (%)