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

Deaths from cardiovascular disease (CVD): Global data

Global: 17.3 million deaths due to CVD Europe: 4 million deaths annually

385,000 people die annually due to CHD in the United States of America

China: 3 million deaths annually

Low- and middleincome countries: Account for 80% of CVD deaths

1. Cardiovascular Diseases (CVDs). WHO Website. http://www.who.int/mediacentre/factsheets/fs317/en/index.html. Accessed April 29, 2013. 2. 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. 3. America's Heart Disease Burden. CDC Website. http://www.cdc.gov/heartdisease/facts.htm. Accessed April 29, 2013. 4. Shou HS, Zhi KL, Lin GR. Outline of the Report on Cardiovascular Disease in China, 2010. Biomed Environ Sci. 2012; 25(3):251-256.

Prevalence of CVD: India

CVD is the largest cause of mortality in India1 Approximately 2 million deaths annually1 The CAD rates among Indians worldwide are 50% to 400% higher than people of other ethnic origins irrespective of gender, religion or social class2 Indians have a high rate of premature CVD3
3.5 3 2.5 2 1.5 1.5 1 0.5 0 All ages 1.1 4 2.3 2.9

26%

2010 2015

32%
0.7 0.9 2

31%

0.3 0.42
< 30 yrs of age

27%

< 50 yrs of age

< 40 yrs of age

Death due to CAD

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 risk factors common in Indians

Risk Factors Abnormal lipids (LDL, HDL, Apo-B, triglycerides) High lipoprotein(a) Low HDL Metabolic syndrome Prevalence 44% 42% 91% 35% men and 50% women

Diabetes, prediabetes
Abdominal obesity, obesity No daily intake of fruits and vegetables Physical inactivity High CRP High homocysteine

17%, 63%
62%, 73%, 50% 94% 65% 41%75%

Diabetes and Dyslipidaemia are among the major risk factors of CVD

1. CADI India: Risk Factor Prevalence. Cadiresearch Website. http://www.cadiresearch.org/topic/asian-indian-heart-disease/cadi-india/risk-factorprevalence. Accessed April 29, 2013.

Prevention and management of CVD

According to WHO, primary prevention and secondary prevention are defined as:

Primary prevention Assessment and management of people with cardiovascular risk factors who have not yet developed CVD

Secondary prevention Management of people with established coronary heart disease (CHD), cerebrovascular disease (CeVD) or peripheral vascular disease or after coronary revascularisation or carotid endarterectomy

1.

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

CVD: Secondary prevention

Secondary prevention: WHO guidelines
Lifestyle advice Smoking cessation and reduction of alcohol intake Dietary changes Physical activity In all patients with BP >140/90 mm Hg Beta-blockers, ACEI, thiazide diuretic All patients with established CHD and/or cerebrovascular disease Treatment with statins is recommended for all patients with established CHD Treatment with a statin should be considered for all patients with established CeVD Other lipid lowering agents are not recommended, either as an alternative to statins or in addition to them Metformin and/or insulin as appropriate Aspirin should be initiated early and continued lifelong in patients with established CHD, or history of TIA or stroke Following Myocardial Infarction (MI) ACE inhibitors are recommended in all patients following MI B-blockers in patients with history of MI and CHD who have developed major LV dysfunction Long-term anticoagulation is recommended for patients with a history of stroke or TIA who are in atrial fibrillation, at low risk of bleeding Patients at moderate and high risk who are likely to have left main stem or triple vessel disease Patients with a previous TIA or non-disabling stroke; severe ipsilateral carotid stenosis (70% 99%) and patients with moderate degrees of stenosis (50%69%)

Antihypertensive drugs

Anticoagulants

Lipid-lowering drugs

Coronary revascularisation

Carotid endarterectomy

Hypoglycaemic drugs Antiplatelet drugs

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

Significance of primary prevention1

Reduces mortality and morbidity

Significance of primary prevention

Decreases the need for coronary revascularisatio n procedures and is costeffective

Extends and improves the quality

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

Assessment
During 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 + Aspirin b) Aspirin c) 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?

Increasing usage of Atorvastatin + Aspirin combination in India 64% 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 recognised Intent to provide Statin at Low Cost
Adverse effects of aspirin are less well recognised in primary prevention, leading to indiscriminate use

1. Client Data on File. 2. APICON Survey. Client Assets on File.

End of the polypill in primary prevention

Polypill was intended for use in both primary and secondary prevention: 1. 2. 3. 4. 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) 3 BP-lowering drugs at half the standard dose (among thiazide diuretics, beta-blockers, ACE inhibitors, ARBs, and calcium channel blockers) Potential advantages of polypill Improved adherence Reduced cost1 Limitations of polypill Adverse effects2 of Aspirin such as GI ulcer and fatal bleeding events
Dr David S Wald (Wolfson Institute of Preventive Medicine, London, UK)

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

In the use of aspirin in a combination product for primary prevention, the benefits are lower than risks, and is not supported by guidelines2

1. 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.

Use of aspirin: What do the guidelines recommend?

According to WHO, primary prevention and secondary prevention are defined as: Primary prevention FDA has not approved the use of aspirin for primary prevention (diabetic and non-diabetic patients)1 Its net benefits in these patients without previous CVD events is controversial2 ESC does not recommend aspirin for primary prevention due to increased risk of major Secondary prevention It is effective as a secondary prevention in diabetic patients with previous history of MI or stroke2

bleeding3

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. ADA. Standards of Diabetes Care 2013. Diabetes care. 2013:36(supplement 1). doi: 10.2337/dc13-S011. 3. 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.

Use of aspirin in diabetic patients: Recommendations

American Diabetes Association1,2 Diabetes is not to be treated as a CHD risk equivalent anymore Was considered as CHD risk (ADA 2003) Not all diabetics need to 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/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 prevention Statins and other therapies should be considered to low the CVD event risk before considering aspirin

1. Standards of Diabetes Care 2013. Diabetes Care. 36(supplement 1). 2. 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).

Aspirin Risk Vs. Benefit in Diabetes

Benefit of aspirin for primary prevention is relatively less in patients with or without diabetes Diabetic patients had a higher rate of bleeding 55% increased bleeding risk among diabetic patients taking aspirin compared with non-diabetic patients2 Aspirin increases major bleeding by 66% and gastrointestinal bleeding by 37% and haemorrhagic stroke by 36%2 1 to 2 major bleeding episodes/year in every 1000 patients treated with low-dose aspirin1
Figure 2. Cumulative Proportion of Patients Developing Major Bleeding Events During Follow-up According to Diabetes Status and Aspirin Use

Cumulative Incidence, per 1000 Person-Years

0.02

Diabetes No aspirin use Aspirin use No diabetes No aspirin use Aspirin use

Diabetes Long-rank P =.85 for aspirin use vs no aspirin use No diabetes Long-rank P<..001 for aspirin use vs no aspirin use

0.01

0 0 1 2 3 4 5 6

Patients with diabetes had a high rate of bleeding that was associated with aspirin use.1

1. Berardis GD et al. Association of aspirin use with major bleeding in patients with or without diabetes. JAMA. 2012;307(21):2286-2294 2. Raju NC, Eikelboom JW. The aspirin controversy in primary prevention. Curr Opin Cardiol 2012, 27:499507

Benefit Vs Risk: Use of Aspirin in primary prevention

Use of aspirin for primary prevention
80% 70% 60% 50% 40% 30% 20% 10%
CVD

66%

36%

37%
Events

0% -10%
10%

Non fatal heart attack

Haemorrhagic Stroke

GI bleeding

Major bleeding

-20%
20 %

-20%

Major bleeding includes: Fatal bleeding, symptomatic bleeding in a critical area or organ, intraspinal, retroperitoneal, pericardial, etc.

1. Aspirin. http://www.cadiresearch.org/topic/medicines/aspirin. Accessed April 10, 2013.

Benefit Vs Risk: Use of Aspirin in primary prevention

A significant proportion (up to 18%) of primary prevention subjects are more likely to derive harm than benefit from indiscriminate aspirin use
Aspirin benefit and harm

Fewer heart attacks

More UGI bleeding and renal failure

Annual coronary event risk For every 1 heart attack prevented, almost two major bleeding events are produced

1. Manes C. Aspirin overprescription in primary cardiovascular prevention. Thromb Res. 2006;118:471-477.

Total costs () incurred due to Aspirin use

Cost incurred during the study period 174.12

Break up of the excess costs 49%

Anti-ulcer drugs, Endoscopies Admissions

36%

126.15
68.82

49.86
18.97 4%

11%

Total for study (2.53 years)

Aspirin

Total/ year of the study

Comparators

Ingredient cost

Dispensing cost

GI complications

Renal complications

1. 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.

PPI adds to the cost

Long term use of Aspirin causes GI irritation (peptic ulcer), requiring use of PPI
A
Incremental Cost per QALY, $

60 000 50 000 40 000 30 000

20 000
10 000 0 -10 000 0.000 0.010 0.020 0.030 0.040 0.050 0.060

B
Incremental Cost per QALY, $

50 000 40 000 30 000 20 0000 10 0000 0 0.000 0.001 0.002 0.003

Incremental Cost per QALY Baseline risk of GI bleeding

0.004

0.005

0.006

0.007

Annual Risk of GI Bleeding Figure 1. Effects of change in baseline gastrointestinal tract (GI) bleeding risk in a 45-year-old man with a 10-year 10% coronary heart disease risk. A, Aspirin vs no treatment. B, Aspirin plus proton pump inhibitor vs aspirin alone, QALY indicated quality-adjusted life-year

PPI is not cost-effective [ADA 2010]2

1. Lanas, M. Polo-Toms, R. Casado-Arroyo. The aspirin cardiovascular/gastrointestinal risk calculator. A tool to aid the clinician. Aliment Pharmacol Ther. 2013;37(7):738-748. 2. Earnshaw SR, Scheiman J, Fendrick M, McDade C, Pignone M. Cost-utility of aspirin and proton pump inhibitors for primary prevention. Arch Intern Med. 2011;171(3):218-225.

Should aspirin be used for primary prevention?

Low-dose aspirin therapy may lead to:1 38.5% of drug-related hospital admissions3 Upper gastro-intestinal tract bleeding Rate of total haemorrhagic events per 1000 person-years is 5.58 (in patients taking aspirin); 3.60 (in those not taking aspirin)4 Rate of bleeding is 5 times higher than expected based on previous studies4

Aspirin has a modest effect on CVD events and is associated with potentially severe adverse effects

1. Aspirin. http://www.cadiresearch.org/topic/medicines/aspirin. Accessed April 10, 2013. 2. 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). 3. Huic M, et al. Adverse drug reactions resulting in hospital admission. Int J Clin Pharmacol Ther. 1994;32(12):675-682. 4. Major Bleeding With Aspirin in Primary Prevention Underestimated . http://www.theheart.org/article/1410099.do. Accessed April 22, 2013.

Is aspirin-statin combination cost-effective?

Actual cost of therapy must include: Cost of PPI that might be added to the aspirin-statin therapy The risk of bleeding and cost of bleeding events including hospitalisations Routine use of PPI is not cost-effective1

Cost of Bleeding Events Cost of PPI

Cost of aspirin + Statin

Cost of Statin

The indiscriminate use of statin-aspirin is mainly because of the low cost of the combination, but the real cost has to be considered
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).

Statin monotherapya safe alternative to Aspirin1,2

Number needed to treat for 1 year to:

Cause a GI* bleed1 Aspirin 248

Cause a fatal GI* bleed1 2066

Cause fatal myositis2 Statins 1,000,000

*GI, gastrointestinal

Statin monotherapy is both safe and effective. Addition of aspirin may introduce unnecessary side effects.

1. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ. 2000;321(7270):1183-1187. 2. Thompson PD, Clarkson P, Karas RH. Statin-Associated Myopathy. JAMA. 2003;289(13):1681-1690.

Statins: More favourable than Aspirin for primary prevention1-4

Statins can reduce the risk of heart attacks and stroke by 35% to 36% Is not associated with side effects especially increased risk of bleeding or stroke Cost effective Addition of aspirin to statin therapy may often result in net harm (stroke/GI bleeding)
Intensive statin therapy in primary prevention

Statin (Rosuvastatin)
Relative risk reduction for cardiovascular event is 4-fold higher than aspirin Absolute risk reduction is 8 times higher (0.59 per 100 person years) than aspirin

Aspirin
Relative risk reduction for cardiovascular event is 12% Absolute risk reduction is 0.07 per 100 person years

Statin alone has a significantly better benefit-risk ratio as compared to aspirin or aspirin/ statin combination
1. Brugts. JJ et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376 2. Tonelli et al. Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. CMAJ. 2011 Nov 8;183(16):E1189202. 3. Aspirin. Website,. Available at http://www.cadiresearch.org/topic/medicines/aspirin. Accessed on April 10, 2013 4. Enas E.A., Hancy Chennikkara Pazhoor MD, Arun Kuruvila MBBS, Krishnaswami Vijayaraghavan MD F. Intensive Statin Therapy for Indians: Part I Benefits. Indian Heart J (In press). 2011.

Benefits of statin monotherapy in primary prevention: Meta-analysis

30%

Reduce with statin use

19% 12%

All cause mortality

Major coronary event

Major cerebrovascular event

Use of statin in patients without established CVD but with cardiovascular risk factors is associated with a significant improvement in survival and a large reduction in the risk of major cardiovascular events

1. 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.

Patient Case 1

Case presentation
50 year old male presents with: Heart burn for the past 2 days Pain in abdomen for the past 3 days Occasional episode of black stool for the past 3 days No history of vomiting Past history Known case of type 2 DM, hypertension for the past 6 months Ramipril 2.5 mg OD Metformin 500 mg BD A combination of aspirin 75 mg and atorvastatin 10 mg OD Family history Father is diabetic and hypertensive; on medications

Physical Examination
Vital Signs: Temperature: 98.4F Pulse: 90 bpm Height: 170 cm; weight: 70 kg BMI: 24.22 Blood pressure: 110/70 mm Hg Respirations: 18 breaths per minute at rest

General Appearance: Fair General Condition: Fair, no signs of dehydration; he is oriented but appears uncomfortable

Head, Ears, Eyes, Nose and Throat (HEENT): Normal

Neurologic Exam: Normal

Lungs: Normal

Cardiac: Normal S1, S2; regular rate and rhythm without murmurs, clicks or rubs

Abdomen/Back: Soft, mild tenderness +, no signs of organomegaly, peritonitis or chronic liver disease; peristaltic sound heard

Investigations
Blood counts Haemoglobin: 10.0 g/dL White blood cell count: 11 109/L Haematocrit: 30% Platelet count: 320 109/L Blood sugar Fasting plasma glucose: 100 mg/dL 2-hour plasma glucose: 120 mg/dL HbA1c: 7.1% Stool examination Occult blood + No presence of ova or cysts Abdominal x-ray Normal Lipid profile Total cholesterol: 190 mg/dL LDL: 110 mg/dL HDL: 41 mg/dL Triglycerides: 143 mg/dL Endoscopy revealed no oesophageal varices and bleeding ulcer

Aspirin-induced upper GI bleed Management Discontinue combination of aspirin 75 mg and atorvastatin 10 mg Initiate rosuvastatin 10 mg OD Continue rest of the medications: Ramipril 2.5 mg OD Metformin 500 mg TID After 5 days of stopping aspirin and atorvastatin combination Faecal occult blood test was negative Patient felt better and comfortable

Case-Based Learning
Irrational use of aspirin and atorvastatin
Is associated with complications (stroke/GI bleeding) Is not cost-effective Cost of bleeding events including hospitalisations

Proper risk stratification in patients with diabetes

Proper assessment of CVD risk is vital Commonly used tool for calculating risk stratification is Framingham Risk Score The CVD risk score of this patient is 13.9% Falls under low risk category (<15%) Statin sufficient for Primary Prevention

Use of rosuvastatin for primary prevention

Is cost-effective Is not associated with side effects [like bleeding or stroke] Is effective for primary prevention in diabetic patients

Case Study
General Aspects Aspirin is not approved for primary prevention in diabetic and non-diabetic patients Statins and other therapies should be considered to lower CVD event risk before considering aspirin

Aspirin Has modest effect on CVD events Relative risk reduction for cardiovascular event is 12% Absolute risk reduction is 0.07 per 100 person-years Is associated with potentially severe adverse effects Is associated with 54% increase risk of GI bleeding when used for primary prevention

Rosuvastatin monotherapy better choice

Rosuvastatin: Combination of aspirin and atorvastatin: Is cost-effective Is not associated with stroke/GI bleeding Relative risk reduction for cardiovascular event is 4fold higher than aspirin Absolute risk reduction is 8 times higher (0.59 per 100 person-years) than aspirin Better benefit-risk ratio as compared with aspirin or aspirin/statin combination

May often result in net harm (stroke/GI bleeding) Is not cost-effective

Discussion

Risk Stratification
Risk assessment: Important for early identification of coronary artery diseases and prioritise treatment1 Need for risk stratification: Individualisation of therapeutic strategies for each patient1,2 Characteristics of any good risk score: Simple and easily accessible Contain all parameters Identify target population that might benefit from a specific treatment Widely used scores: Framingham, SCORE, TIMI, GRACE and PURSUIT

1. Ginghina C, et al. J Med Life. 2011;4(4):377-386. 2. Erbel R, et al. J Am Coll Cardiol. 2010;56(17):1397-1406.

Framingham Risk Score

FRS applies to assessment of primary prevention of CHD Categorisation of 10 year Risk of CHD Event Very low risk Low risk Moderate risk High risk < 10% < 15% 15-20% > 20%

1. Framingham risk score. West Hertfordshire Cardiology Website. Accessed April 30, 2013.

Patient Case 2

Case Presentation
Presenting complaints A 46 year old female was brought to the ED with complaints of Acute left sided weakness Impaired vision on the left visual field Past history Known case of type 2 DM with dyslipidaemia, since 1 year, now on: Metformin 500 mg BD Combination of aspirin 75 mg and atorvastatin 10 mg OD

Physical Examination
Vital Signs Temperature: 98.6F Height: 162 cm Weight: 70 kg BMI: 26.7 kg/m2 Pulse: 88 bpm RR: 22 breaths per minute BP: 130/80 mm Hg

General Appearance: Conscious. Oriented to time, place and person

Head, Ears, Eyes, Nose and Throat (HEENT): Normal

Neurologic Exam: Left homonymous hemianopsia Left sided weakness of the face, arm and leg with strength 4/5 Left hemi-sensory loss Cardiac: Normal S1, S2; regular rate and rhythm without murmurs, clicks or rubs

Lungs: Normal

Abdomen/Back: Soft, no signs of organomegaly, peritonitis or chronic liver disease. Peristaltic sound heard

Lab Investigations

Test CBC, ESR Blood glucose levels Total cholesterol HDL-C Triglycerides LDL-C Non-HDL-C Emergency CT scan ECG Chest x-ray

Result Hb: 10.6 g/dL; TC: 11000/L; ESR: 25 mm/h FBS: 108 mg/dL; PPBS: 180 mg/dL; 200 mg/dL 38 mg/dL 170 mg/dL 128 mg/dL 162 mg/dL Right parieto-occipital haemorrhage Sinus rhythm NAD

Diagnosis and Management

Right parieto-occipital haemorrhage with known case of type 2 diabetes with dyslipidemia Aspirin is suspected to be cause of haemorrhagic stroke
Management Aspirin stopped The patient was stabilised and 2 units of platelet concentrate was infused The CVD risk score of this patient is 10 % Falls under low risk category (<15%) Statin sufficient for Primary Prevention After stabilisation: Initiate rosuvastatin 10 mg OD Continue metformin 500 mg OD Lifestyle modifications Advised early mobilisation

Follow-up
General examination
Conscious and well oriented to time, place and person Improvement in vision No weakness of the face, arm and leg, with strength 5/5 Pulse: 72 bpm RR: 18 breaths per minute BP: 128/70 mm Hg

Test CBC, ESR Blood glucose levels Total cholesterol HDL-C Triglycerides LDL-C

Result Hb: 11.2 g/dL; TC: 9250/L; ESR: 19 mm/h FBS: 96 mg/dL; PPBS: 125 mg/dL 185 mg/dL 42 mg/dL 110 mg/dL 121 mg/dL

Non-HDL-C

143 mg/dL

Discussion

Risk of haemorrhagic stroke with Aspirin

Haemorrhagic Stroke in Primary Prevention Trials
Events / Patients (%) 5.00% 4.00% 3.00% 2.00% 1.00% 0.00%
Physicians Health study (PHS) British Doctors Trial (BDT) Thrombosis Prevention Trial (TPT)gory 3 Hypertension Optimal Treatment (HOT) Primary Preventio n Project (PPP) Early Treatment Diabetic Retinopathy Study (ETDRS)

Aspirin

Control

Excess haemorrhagic stroke events have been attributed to aspirin therapy

1. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.

Gender differences in stroke fatality

Figure: Gender-specific mortality-adjusted cumulative incidence (lifetime risk) of stroke. 1

%
25

Women are more likely than men to have worse functional outcomes and poorer quality of life following stroke2

Cumulative Incidence

Women LTR 20 15 Men LTR

10
5 0

45

50

55

60

65

70

75

80

85

90

95

Age

1. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke. 2009;40:1032-1037. 2. Schumacher HC, Bateman BT, Boden-Albala B et al. Use of thrombolysis in acute ischemic stroke: analysis of the nationwide inpatient sample 1999 to 2004. Ann. Emerg. Med. 2000; 50:99-107.

Use of statins in diabetic patients1-3

Meta-analysis of 10 primary prevention trials with 23% of diabetic patients 12% reduction in all-cause mortality 30% reduction in MACE 19% reduction in stroke Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients [ADA 2012] with overt CVD. without CVD who are over the age of 40 years and have one or more other CVD risk factors.
Relative risk Reduction (%) 25

n CARE 586

End point Death, MI Death, MI, unstable angina pectoris, heart failure, stroke, revascularisation Major coronary event, stroke, revascularisation Death, MI, revascularisation Death, MI, revascularisation Death, MI Death, MI

GREACE

313

58

HPS

3050

18

LIPID LIPS 4S 4S

782 202 202 483

19 47 55 42

MI, Myocardial infarction. Table: Relative risk reduction on the primary end points by statin treatment in diabetic subjects

Statins are recommended to reduce cardiovascular risk in diabetes- Class 1 A recommendation, ESC 20124
1. Macchia A et al. Statins but Not Aspirin Reduce Thrombotic Risk Assessed by Thrombin Generation in Diabetic Patients without Cardiovascular Events: The RATIONAL Trial. PLoS One. 2012;7(3):e32894. doi: 10.1371/journal.pone.0032894. Epub 2012 Mar 28. 2. Wienbergen H. Should we prescribe Statin and Aspirin for Every Diabetic Patient? Diabetes Care; Volume 31, suppl 2, Febuary 2008: S222-225 3. Enas E.A., Hancy Chennikkara Pazhoor MD, Arun Kuruvila MBBS, Krishnaswami Vijayaraghavan MD F. Intensive Statin Therapy for Indians:Part I Benefits.Indian Heart J (In press) Indian Heart J (In press). 2011. 4. Perk J, De BG, Gohlke H, et al.G Ital Cardiol (Rome). 2013;14(5):328-392.

Rosuvastatin: Effective statin for diabetics

Incidence of myocardial infarction, stroke or death from CV causes during JUPITER trial
0.08 0.06 Placebo 0.04
Rosuvastatin

Risk reduction with rosuvastatin

0.02 0.00 Years

47% reduction in MI, stroke or death due to CV cause

Arterial revascularisation or hospitalisation for unstable angina Arterial revascularisation 46

47

Stroke 0.08 47% reduction in arterial revascularisation or hospitalisation for unstable angina

48

0.06
0.04

Placebo
Rosuvastatin

Myocardial infarction

54

42

44

46

48

50

52

54

56

0.02 % risk reduction 0.00 Years

Rosuvastatin is effective for primary prevention in diabetic patients

1. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.

Rosuvastatin: JUPITER subgroup analysis

JUPITER study subgroup analysis in women
73 80 70 58 60 46 50 40 30 20 23 37 37 63 76

10
0 Myocardial infarction Stroke

Arterial Arterial revascularisation revascularisation or hospitalisation for unstable angina

% reduction compared with placebo (Women) % reduction compared with placebo (Men)

The risk reduction with rosuvastatin is significantly more compared with placebo across different sub-groups

1. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.

Primary prevention of CVD: Way forward

Framingham Risk Score Very low risk <10% Low risk < 15% Moderate risk 15%-20% High risk >20% Recommended Statin Statin Statin Statin; Aspirin can be added

Most of the patients frequently presenting to our clinic will be aged 50 yrs, have concomitant diabetes, hypertension & h/o smoking. As per the Framingham, they fall under moderate risk where Statin alone is sufficient.

1. Executive Summary: Standards of Medical Care in Diabetes 2012. Diabetes Care January 2012 vol. 35 no. Supplement 1 S4-S10

Primary prevention of CVD: Way forward

Based on the current disease burden and treatment practices, following gaps in care need to be addressed There is overuse of aspirin in primary prevention despite lack of evidence and change in guidelines Most patients fall under mild and moderate risk where statin alone will suffice Combined use of atorvastatin-aspirin despite no synergetic benefits, is in fact doing more harm Haemorrhagic stroke has increased incidence in aspirin users and has a higher fatality rate in women Rosuvastatin monotherapy has high efficacy and safety, and can be an optimum therapy for primary prevention of CVD

Thank You
This CME is brought to you by:

Back-up slides

Diabetes and dyslipidaemia

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Male

Female 65.0% 56.7%

86.5%
79.2%

Prevalence (%)

50.7% 47.6%

36.8%

29.0%

Elevated TC

Raised LDL-C

Low HDL-C

Elevated TG

Prevalence of lipid abnormalities

There is a high prevalence of dyslipidaemia in India among patients with diabetes

1. Gupta S. Editorial. Int J Diab Dev Ctries. 2004;24(3):58-64.

Management of Diabetic dyslipidaemia

The American Diabetes Association guidelines also consider LDL-C as the primary target of therapy
Diabetes

Lifestyle modification

Without overt CVD

With overt CVD

Age >40 years, with >1 other CVD risk factor(s)

Age <40 years

LDL-C >100 mg/dL

>1 other CVD risk factors

Statin

1. Standards of Medical Care in Diabetes-2009. Diabetes Care. 2009;32(suppl 1):S13-S61.