update on antiplatelet therapy in the treatment and prevention of cardiovascular disease

UPDATE ON ANTIPLATELET UPDATE ON ANTIPLATELET THERAPY IN THE TREATMENT THERAPY IN THE TREATMENT

AND PREVENTION OF AND PREVENTION OF CARDIOVASCULAR DISEASECARDIOVASCULAR DISEASE

Charles H Hennekens, MD, DrPHCharles H Hennekens, MD, DrPHSir Richard Doll Research Professor of MedicineSir Richard Doll Research Professor of Medicine

Charles E. Schmidt College of Medicine Charles E. Schmidt College of Medicine Florida Atlantic UniversityFlorida Atlantic University

Clinical Professor of Preventive MedicineClinical Professor of Preventive MedicineNova Southeastern UniversityNova Southeastern University

Voluntary Professor of Family Medicine and Community HealthVoluntary Professor of Family Medicine and Community HealthUniversity of Miami Miller School of Medicine University of Miami Miller School of Medicine

Dr. Hennekens receives investigator initiated research grant support from Bayer to the Charles Dr. Hennekens receives investigator initiated research grant support from Bayer to the Charles E. Schmidt College of Medicine at Florida Atlantic University.E. Schmidt College of Medicine at Florida Atlantic University.

He serves as an independent scientist in an advisory role to investigators and He serves as an independent scientist in an advisory role to investigators and sponsors, including as Chair or member of Data and Safety Monitoring Boards to sponsors, including as Chair or member of Data and Safety Monitoring Boards to Actelion, Amgen, Anthera, Bayer, Bristol-Myers Squibb, Canadian Institutes of Actelion, Amgen, Anthera, Bayer, Bristol-Myers Squibb, Canadian Institutes of Health Research, Dainippon-Sumitomo, National Association for Continuing Health Research, Dainippon-Sumitomo, National Association for Continuing Education,, Pozen, Pfizer, PriMed, United States (US) Food and Drug Education,, Pozen, Pfizer, PriMed, United States (US) Food and Drug Administration, U.S.National Institutes of Health, and UpToDate. Administration, U.S.National Institutes of Health, and UpToDate.

He serves as an independent scientist in an advisory role to legal counsel for He serves as an independent scientist in an advisory role to legal counsel for GlaxoSmithKline and Stryker.GlaxoSmithKline and Stryker.

He serves as speaker for the Association for Research in Vision and He serves as speaker for the Association for Research in Vision and Ophthalmology, AstraZeneca, International Atherosclerosis Society, and Pfizer. Ophthalmology, AstraZeneca, International Atherosclerosis Society, and Pfizer.

He receives royalties for authorship or editorship of three textbooks and as co-He receives royalties for authorship or editorship of three textbooks and as co-inventor on patents held by Brigham and Women’s Hospital concerning inventor on patents held by Brigham and Women’s Hospital concerning inflammatory markers for cardiovascular disease.inflammatory markers for cardiovascular disease.

He has an investment management relationship with The West-Bacon Group within He has an investment management relationship with The West-Bacon Group within SunTrust Investment Services who has sole discretionary investment authority. SunTrust Investment Services who has sole discretionary investment authority.

He owns no common or preferred stock in any pharmaceutical or device industry.He owns no common or preferred stock in any pharmaceutical or device industry.

DisclosureDisclosure

Death is inevitable but Death is inevitable but

premature death is not.premature death is not.

Sir Richard Doll Sir Richard Doll

OBJECTIVESOBJECTIVES

Aspirin in the treatment of CVDAspirin in the treatment of CVD Additive benefits of aspirin and Additive benefits of aspirin and

statinsstatins Aspirin in the prevention of CVD Aspirin in the prevention of CVD Dual antiplatelet therapy in CVDDual antiplatelet therapy in CVD Newer antiplatelet agents in CVDNewer antiplatelet agents in CVD

Milestones For AspirinMilestones For Aspirin5th century BC5th century BC HippocratesHippocrates

1897 AD1897 AD Felix Hoffman/Friedrich Bayer synthesize aspirinFelix Hoffman/Friedrich Bayer synthesize aspirin

2020thth Century Aspirin becomes the most widely used drug in the world for Century Aspirin becomes the most widely used drug in the world for pain reliefpain relief

1971 John Vane discovers CVD mechanism1971 John Vane discovers CVD mechanism

19881988 Physician’s Health Study shows aspirin prevents first MIPhysician’s Health Study shows aspirin prevents first MI

1988 APT shows aspirin decreases MI, stroke, and CVD death for 1988 APT shows aspirin decreases MI, stroke, and CVD death for survivors of MI and strokesurvivors of MI and stroke

1988 ISIS-2 shows aspirin decreases mortality during acute MI 1988 ISIS-2 shows aspirin decreases mortality during acute MI

Moses Receiving The Tablets Moses Receiving The Tablets From GodFrom God

Milestones For AspirinMilestones For Aspirin5th century BC5th century BC HippocratesHippocrates

1897 AD1897 AD Felix Hoffman/Friedrich Bayer synthesize aspirinFelix Hoffman/Friedrich Bayer synthesize aspirin

2020thth Century Aspirin becomes the most widely used drug in the world for Century Aspirin becomes the most widely used drug in the world for pain reliefpain relief

1971 John Vane discovers CVD mechanism1971 John Vane discovers CVD mechanism

19881988 Physician’s Health Study shows aspirin prevents first MIPhysician’s Health Study shows aspirin prevents first MI

1988 APT shows aspirin decreases MI, stroke, and CVD death for 1988 APT shows aspirin decreases MI, stroke, and CVD death for survivors of MI and strokesurvivors of MI and stroke

1988 ISIS-2 shows aspirin decreases mortality during acute MI 1988 ISIS-2 shows aspirin decreases mortality during acute MI

The Most Plausible Mechanism Of The Most Plausible Mechanism Of Aspirin In Reducing Risks Of Aspirin In Reducing Risks Of Cardiovascular DiseaseCardiovascular Disease

Aspirin irreversibly acetylates the activeAspirin irreversibly acetylates the active

site of cyclooxygenase, which is requiredsite of cyclooxygenase, which is required

for the production of thromboxane A2, afor the production of thromboxane A2, a

powerful promoter of platelet aggregationpowerful promoter of platelet aggregation

Vane JR. Inhibition of prostaglandin synthesis as a mechanism of Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action of aspirin like drugs. Nat New Biol. 1971;231:232-5.action of aspirin like drugs. Nat New Biol. 1971;231:232-5.

Hennekens. Epidemiology in Medicine. 1987.

Totality Of EvidenceTotality Of Evidence

Basic research (why)Basic research (why) Epidemiology (whether)Epidemiology (whether)

descriptive studiesdescriptive studiescase reportscase reportscase seriescase seriesecological studiesecological studies

analytic studiesanalytic studiesobservationalobservational

case-controlcase-control cohortcohort

randomized trialsrandomized trials

Observational Epidemiologic StudiesObservational Epidemiologic Studies

Some but not all case-control & cohort studies Some but not all case-control & cohort studies indicate that individuals and/or their health care indicate that individuals and/or their health care providers who self-select for aspirin have lower risks providers who self-select for aspirin have lower risks of CVD. of CVD.

For most epidemiologic hypotheses, randomized For most epidemiologic hypotheses, randomized trials are neither necessary nor desirabletrials are neither necessary nor desirable

For small to moderate effects, however, theFor small to moderate effects, however, theonly reliable design strategy is the large randomizedonly reliable design strategy is the large randomizedtrial because the amount of uncontrolled & trial because the amount of uncontrolled & uncontrollable confounding factors inherent in uncontrollable confounding factors inherent in observational studies can be as large as the effect observational studies can be as large as the effect sizessizes

Hennekens CH, DeMets D: The need for large scale randomized evidence Hennekens CH, DeMets D: The need for large scale randomized evidence without undue emphasis on small trials, their meta-analyses or subgroup analyses JAMA without undue emphasis on small trials, their meta-analyses or subgroup analyses JAMA 20092009

Evolution of Antiplatelet (AP) Therapy TrialsEvolution of Antiplatelet (AP) Therapy Trials

Year No Of Trials No Of Patients

1988 25 25,000

1997 194 212,000

AP vs control (135,000)

Different AP (77,000)

Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71.

Aspirin in the Treatment of CVDAspirin in the Treatment of CVD

In a wide range of patients who have In a wide range of patients who have survived a prior occlusive event (including survived a prior occlusive event (including MI, occlusive stroke or transient ischemic MI, occlusive stroke or transient ischemic attack, or other high risk categories attack, or other high risk categories including unstable and stable angina, including unstable and stable angina, angioplasty, or coronary artery bypass angioplasty, or coronary artery bypass graft), antiplatelet therapy, principally with graft), antiplatelet therapy, principally with aspirin, prevents ~25% of serious vascular aspirin, prevents ~25% of serious vascular events, including significant reductions on events, including significant reductions on MI, stroke, and CVD death. MI, stroke, and CVD death.

All these patients have 10-year risks of CHD All these patients have 10-year risks of CHD of 20% or more based on the Framingham of 20% or more based on the Framingham risk score recommended by the US NHLBI.risk score recommended by the US NHLBI.

AntiThrombotic Trialists Collaboration. Lancet, 2002

Benefits of Aspirin on Risk of StrokeBenefits of Aspirin on Risk of Stroke

In 158 trials, there were 3,522 nonfatal and In 158 trials, there were 3,522 nonfatal and 1,424 fatal strokes after randomization.1,424 fatal strokes after randomization.

Antiplatelet therapy, principally with aspirin, Antiplatelet therapy, principally with aspirin, reduced stroke by about 25%,reduced stroke by about 25%, regardless of regardless of whether the patient entered the trial with prior whether the patient entered the trial with prior MI, stroke, TIA, or other high-risk conditions.MI, stroke, TIA, or other high-risk conditions.

Antiplatelet therapy, principally with aspirin, Antiplatelet therapy, principally with aspirin, increases the absolute risk of hemorrhagic increases the absolute risk of hemorrhagic stroke by 3 per 10,000 treated patients. The stroke by 3 per 10,000 treated patients. The upper bound of the 95% confidence interval is upper bound of the 95% confidence interval is less than 1 per 1000 treated patients.less than 1 per 1000 treated patients.


ISIS-2 Collaborative Croup Lancet. 1988 Aug 13;332: 349-60.

Second International Study of Infarct Survival

Hypothesis: Additive Benefits of Hypothesis: Additive Benefits of Statins and Aspirin to Decrease Statins and Aspirin to Decrease Risks of CVDRisks of CVD

ATHEROSCLEROSIS ATHEROSCLEROSIS The principal underlying cause of occlusive The principal underlying cause of occlusive

CVD eventsCVD events which is inhibited by statinswhich is inhibited by statins

THROMBOSISTHROMBOSIS The principal proximate cause of occlusive The principal proximate cause of occlusive

CVD eventsCVD events which is inhibited by aspirinwhich is inhibited by aspirin

Hebert P, Pfeffer MA, Hennekens CH: Use of Statins and Aspirin to Decrease Risks of Hebert P, Pfeffer MA, Hennekens CH: Use of Statins and Aspirin to Decrease Risks of CVD J CV Pharm Ther. 2002;7:77-80CVD J CV Pharm Ther. 2002;7:77-80

A meta-analysis of 5 trials in secondary prevention of CVD of over A meta-analysis of 5 trials in secondary prevention of CVD of over 15,000 patients with over 73,000 patient-years of observation 15,000 patients with over 73,000 patient-years of observation demonstrated that the combination of aspirin and statins provided demonstrated that the combination of aspirin and statins provided statistically significant and clinically important additive benefits for statistically significant and clinically important additive benefits for the prespecified individual endpoints of fatal or non-fatal MI as well the prespecified individual endpoints of fatal or non-fatal MI as well as ischemic stroke and a combined endpoint of CHD death, non-as ischemic stroke and a combined endpoint of CHD death, non-fatal MI, CABG, PTCA or ischemic stroke:fatal MI, CABG, PTCA or ischemic stroke:

The probability of synergy (i.e. greater than additive benefits) was The probability of synergy (i.e. greater than additive benefits) was 0.92. 0.92.

These statistically significant and clinically important benefits were These statistically significant and clinically important benefits were also present in individual analyses of data from the LIPID and CARE also present in individual analyses of data from the LIPID and CARE trialstrials

Summary: Additive Benefits of Aspirin and Summary: Additive Benefits of Aspirin and Statins in Secondary Prevention of CVDStatins in Secondary Prevention of CVD

Hennekens CH, et al. Arch Int Med, 2001.Hennekens CH, et al. Arch Int Med, 2001.

Hennekens CH et al. Arch Int Med 2004; 164:945-948.

Relative Risk (95% CI) RRR

Prava+ASA vs ASA Alone

Prava+ASA vs Prava Alone

Fatal or Non-Fatal MI

0.400 0.800 1.0000.600

0.400 0.800 1.0000.600

CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke



24%0.76

13%0.87

31%0.69

26%0.74



29%0.71

31%0.69

Ischemic Stroke

0.400 0.800 1.0000.600

Greater Relative Risk Reductions (RRR) for Greater Relative Risk Reductions (RRR) for Pravastatin (Prava) + Aspirin (ASA)Pravastatin (Prava) + Aspirin (ASA)

versus Prava or ASA alone versus Prava or ASA alone

Summary: Aspirin in Primary Prevention of CVDSummary: Aspirin in Primary Prevention of CVD In a comprehensive worldwide meta analysis of the 6 randomized In a comprehensive worldwide meta analysis of the 6 randomized

trials of primary prevention aspirin produces a statistically significant trials of primary prevention aspirin produces a statistically significant and clinically important reduction in risk of a first myocardial infarction and clinically important reduction in risk of a first myocardial infarction by about 1/3 but the available data on stroke and cardiovascular by about 1/3 but the available data on stroke and cardiovascular death remain inconclusivedeath remain inconclusive

In these apparently healthy men and women at low risk aspirin is of In these apparently healthy men and women at low risk aspirin is of uncertain net value as the reduction in occlusive events needs to be uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds.weighed against any increase in major bleeds.

The average 10 year risk of a first CHD event among the apparently The average 10 year risk of a first CHD event among the apparently healthy men and women in the 6 randomized trials is less than 5%.healthy men and women in the 6 randomized trials is less than 5%.

The chief need is for randomized evidence in apparently healthy The chief need is for randomized evidence in apparently healthy individuals whose 10 year risk of a first CHD event is 10-19%. individuals whose 10 year risk of a first CHD event is 10-19%.

Until then any decision to use aspirin in primary prevention should be Until then any decision to use aspirin in primary prevention should be an individual clinical judgement by the healthcare provider. an individual clinical judgement by the healthcare provider.

Writing Group (Baigent C, Blackwell L, Buring J, Collins R, Emberson J, Godwin J, Writing Group (Baigent C, Blackwell L, Buring J, Collins R, Emberson J, Godwin J, Hennekens C, Kearney P, Meade T, Patrono C, Peto R, Roncaglioni R, Zanchetti A). Aspirin Hennekens C, Kearney P, Meade T, Patrono C, Peto R, Roncaglioni R, Zanchetti A). Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data. Lancet. 2009;373:1849-60.individual participant data. Lancet. 2009;373:1849-60.

10-Year Risk of a First CHD Event in 10-Year Risk of a First CHD Event in the Six Major Trials of Aspirin in the Six Major Trials of Aspirin in

Primary Prevention of CVDPrimary Prevention of CVD

WHSWHS 2.5%2.5%

HOTHOT 3.6%3.6%

PPPPPP 4.3%4.3%

PHSPHS 4.8%4.8%

BMDBMD 8.9%8.9%

TPTTPT 12.4%12.4%

Dose Of Aspirin: Dose Of Aspirin: Indirect ComparisonsIndirect Comparisons

% Reduction Regimen No Trials (SE) 3P value

Aspirin Alone (mg)

500-1500 34 19 (3) <0.00001

160-325 19 26 (3) <0.00001

75-150 12 32 (6) <0.0001

<75 3 13 (8) NS

Total 68 23 (2) <0.0001X3

2 het = 8.2, P=.04.

..AntiThrombotic Trialists Collaboration. Lancet, 2002

Time To Achieve Maximal Inhibition Of Time To Achieve Maximal Inhibition Of Serum Thromboxane BSerum Thromboxane B22 With 75 mg ASA With 75 mg ASA

Hennekens CH and Schneider W. Expert Rev Cardiovasc Ther. 2008; 6: 95-107

Indirect and Direct Comparisons Between Indirect and Direct Comparisons Between Daily Aspirin Doses of 325mg or less and Daily Aspirin Doses of 325mg or less and Major Extracranial Bleeding in the Secondary Major Extracranial Bleeding in the Secondary Prevention TrialsPrevention Trials

Indirect comparisons: In meta-analyses of Indirect comparisons: In meta-analyses of trials of daily aspirin doses of 325mg or trials of daily aspirin doses of 325mg or less (160-325, 75-160, or <75), risks of less (160-325, 75-160, or <75), risks of major extracranial bleeds were similar.major extracranial bleeds were similar.

Direct comparisons: In the two trials that Direct comparisons: In the two trials that directly compared daily aspirin doses of directly compared daily aspirin doses of 75-325mg with <75mg, risks of major 75-325mg with <75mg, risks of major extracranial bleeds were similarextracranial bleeds were similar..


Optimal Dosing For Aspirin In CHDOptimal Dosing For Aspirin In CHD

Secondary Prevention& 75 mg – 325 mg

Primary Prevention

Acute CVD Syndrome 162.5 mg – 325 mg

Hennekens CH, Dyken M, Fuster V:Circ. 1997

Effects On PlateletsEffects On PlateletsASAASA Irreversible inhibitionIrreversible inhibition

NSAIDSNSAIDS Reversible inhibition Reversible inhibition Possible but unproven small Possible but unproven small clinical CVD benefits of clinical CVD benefits of naproxen naproxen Possible but unproven Possible but unproven inhibition of clinical CVD inhibition of clinical CVD benefits of aspirin by ibuprofenbenefits of aspirin by ibuprofen

COXIBSCOXIBS Prothrombotic effects Prothrombotic effects and risks of similar and risks of similar magnitude to NSAIDS magnitude to NSAIDS on CVDon CVD

AcetaminophenAcetaminophen No effects on platelets No effects on platelets but risks on liver and but risks on liver and kidneyskidneys

Hennekens CH, Borzak S: JCPT, 2008

Dose-Dependent Side Effects of Dose-Dependent Side Effects of

AspirinAspirin

The 5 Year UK-TIA Trial of about 2400The 5 Year UK-TIA Trial of about 2400

Side Effects Placebo 300 mg 1200 mg

GI Symptoms 25% 29% 39%

GI bleeding requiring transfusion 1.6% 2.6% 4.9%

Warlow C. et al. BMJ, 1988

Possible Additional Beneficial Possible Additional Beneficial Mechanisms of Action of Higher Mechanisms of Action of Higher

Doses of Aspirin on CVDDoses of Aspirin on CVD

Enhance nitric oxide formationEnhance nitric oxide formation Decrease inflammationDecrease inflammation Stabilize endothelial functionStabilize endothelial function

Hennekens CH, Sechenova, O, Hollar D, Serebruany VL. Dose of Aspirin in the Treatment and Prevention of Cardiovascular Disease: Current and Future Directions. JCPT 2006.Hennekens CH, et al. A randomized trial of aspirin at usual clinical doses and increased nitric oxide formation in humans. JCPT 2010.

Lack of Sex Differences in Response Lack of Sex Differences in Response to Aspirin: to Aspirin: ATT Patients with Prior MI or ATT Patients with Prior MI or

StrokeStroke

Endpoint MenWomen

Major coronary events 19% 25%

Stroke 17% 22%

Percent Reductions

Hennekens CH, Hollar D, Baigent C. Sex differences in response to aspirin in CVD: an hypothesis formulated but not tested. Nature: Cardiovascular Medicine 2006,3:4-5

Dual Antiplatelet Dual Antiplatelet TherapyTherapy

Risks versus MonotherapyRisks versus Monotherapy Benefits and risks:Benefits and risks:

Aspirin + DipyrimadoleAspirin + Dipyrimadole

Aspirin + ClopidogrelAspirin + Clopidogrel

Issues with ClopidogrelIssues with Clopidogrel

Clopidogrel versus PrasugrelClopidogrel versus Prasugrel

Clopidogrel versus TicagrelorClopidogrel versus Ticagrelor

DUAL ANTIPLATELET THERAPY AND DUAL ANTIPLATELET THERAPY AND INCREASED RISKS OF BLEEDINGINCREASED RISKS OF BLEEDING

In a meta-analysis of 18 randomized trials which In a meta-analysis of 18 randomized trials which included 129,314 patientsincluded 129,314 patients

Those assigned to dual antiplatelet therapy have about a Those assigned to dual antiplatelet therapy have about a 50% increase in risks of major bleeding compared with 50% increase in risks of major bleeding compared with those given single agent therapythose given single agent therapy

The magnitude of these excess risks are about as high The magnitude of these excess risks are about as high as the approximately 60% increase observed in the trials as the approximately 60% increase observed in the trials comparing single antiplatelet agents to placebo comparing single antiplatelet agents to placebo

These excess risks of major bleeding should be These excess risks of major bleeding should be considered in relation to the benefits on occlusive CVD considered in relation to the benefits on occlusive CVD events in choosing the optimal antiplatelet strategy, events in choosing the optimal antiplatelet strategy, especially for long-term treatment of patients with prior especially for long-term treatment of patients with prior events or those at high risk of developing CVD.events or those at high risk of developing CVD.

Fund Clin Pharm 2008; 22:315-321Fund Clin Pharm 2008; 22:315-321

Aspirin + Dipyrimadole:Aspirin + Dipyrimadole:Second European Stroke Study (ESPS-2)Second European Stroke Study (ESPS-2)

Randomized, double-blind placebo controlled 2x2 Randomized, double-blind placebo controlled 2x2 factorial trialfactorial trial

6602 patients with prior ischemic stroke or TIA6602 patients with prior ischemic stroke or TIA ASA (25mg bid) and/or dipyrimadole (200mig bid ASA (25mg bid) and/or dipyrimadole (200mig bid

sustained release)sustained release) Deaths from stroke were reducedDeaths from stroke were reduced

13% by ASA (p=0.016)13% by ASA (p=0.016)

15% by dipyrimadole (p=0.039)15% by dipyrimadole (p=0.039)

24% by the combination of ASA and 24% by the combination of ASA and dipyrimadole dipyrimadole

(p<0.001)(p<0.001)Diener, HC et al J Neurol Sci .1996 Nov; 143: (1-2)1-13

Aspirin + Dipyridamole: Aspirin + Dipyridamole: PROFESSPROFESS

20,332 post-ischemic stroke patients 20,332 post-ischemic stroke patients within 120 dayswithin 120 days

Randomized to aspirin 25mg +extended Randomized to aspirin 25mg +extended release dipyrimadole 200mg bid vs release dipyrimadole 200mg bid vs clopidogrel 75mg qdclopidogrel 75mg qd

After 2.5 years there were similar rates of After 2.5 years there were similar rates of the primary prespecified composite the primary prespecified composite endpoint of stroke, MI or vascular death.endpoint of stroke, MI or vascular death.

NEJM, 2008;359:1238-1251NEJM, 2008;359:1238-1251

Clopidogrel + Aspirin Clopidogrel + Aspirin

Clopidogrel adds to the benefit of aspirin in Clopidogrel adds to the benefit of aspirin in

some circumstances.some circumstances.

CURE, a randomized trial of acute MI, CURE, a randomized trial of acute MI, showed that clopidogrel adds to the showed that clopidogrel adds to the benefit of aspirin on CVD events but benefit of aspirin on CVD events but increased major bleeding. increased major bleeding.

COMMIT/CCS-2, a randomized trial of acute COMMIT/CCS-2, a randomized trial of acute coronary syndromes in China, showed that coronary syndromes in China, showed that clopidogrel adds to the benefit of aspirin clopidogrel adds to the benefit of aspirin on CVD and total mortality but did not on CVD and total mortality but did not increase major bleeding.increase major bleeding.

CURE Trial Investigators NEJM. 2001;345: 494-502

Second Chinese Cardiac Study: Second Chinese Cardiac Study: COMMITCOMMIT

Randomized, double-blind, 2x2 factorial trial Randomized, double-blind, 2x2 factorial trial of clopidogrel and metoprololof clopidogrel and metoprolol

45,852 patients within 24 hours of onset of 45,852 patients within 24 hours of onset of symptoms of suspected acute myocardial symptoms of suspected acute myocardial infarctioninfarction

Randomization in clopidogrel arm to daily Randomization in clopidogrel arm to daily 75mg clopidogrel+162mg aspirin(22,960) or 75mg clopidogrel+162mg aspirin(22,960) or placebo +160mg aspirin(22,891)placebo +160mg aspirin(22,891)

COMMIT Collaborative Group. Lancet 2005; 366: 1607-1621.


COMMIT Clopidogrel Arm: COMMIT Clopidogrel Arm: Primary OutcomesPrimary Outcomes

End pointEnd point Clopidogrel,Clopidogrel,n=22n=22 961 961 (%)(%)

Placebo, Placebo, n=22n=22 891 891 (%)(%)

Odds ratio Odds ratio (95% CI)(95% CI)

P P valuevalue

Death/MI/Death/MI/stroke stroke

9.29.2 10.110.1 0.910.91(0.86-0.97)(0.86-0.97)

0.0020.002

Death from Death from any causeany cause

7.57.5 8.18.1 0.930.93(0.87-0.99)(0.87-0.99)

0.030.03

COMMIT: Major Bleeding COMMIT: Major Bleeding


BleedingBleeding Clopidogrel Clopidogrel (%)(%)

Placebo Placebo (%)(%)

Excess Excess per 1000per 1000

pp

Any major Any major bleedbleed

0.580.58 0.550.55 0.40.4 0.590.59

CHARISMACHARISMA

A randomized, double-blind placebo controlled trial of A randomized, double-blind placebo controlled trial of 15,603 patients (79% ) with established CVD and 21% 15,603 patients (79% ) with established CVD and 21% with multiple risk factors designed to test whether with multiple risk factors designed to test whether clopidogrel should be continued beyond 1 year in addition clopidogrel should be continued beyond 1 year in addition to aspirin.to aspirin.

All patients received daily aspirin(75-162mg) and were All patients received daily aspirin(75-162mg) and were randomized to daily clopidogrel(75mg) or placebo randomized to daily clopidogrel(75mg) or placebo

Clopidogrel patients had an event rate of 6.8% and Clopidogrel patients had an event rate of 6.8% and placebo patients had an event rate of 7.3%. placebo patients had an event rate of 7.3%.

CHARISMA demonstrated CHARISMA demonstrated no significant benefit long term no significant benefit long term when clopidogrel is added to aspirin. when clopidogrel is added to aspirin.

Rates of severe bleeding were similar but clopidogrel Rates of severe bleeding were similar but clopidogrel patients experienced significantly higher rates of patients experienced significantly higher rates of moderate bleeding. moderate bleeding.

There was possible effect modification by presence or There was possible effect modification by presence or absence of prior events, a post hoc formulated hypothesis absence of prior events, a post hoc formulated hypothesis not directly tested in this trial.not directly tested in this trial.Bhatt DL, et al; N Engl J Med. 2006. 54: 1706-1717

ISIS-2 Investigators, Lancet, 1988

Issues with ClopidogrelIssues with Clopidogrel

Onset: 4-6 hours Onset: 4-6 hours (after loading dose with 8 x (after loading dose with 8 x maintenance dose)maintenance dose)

Offset: 5-7 daysOffset: 5-7 days Variable response: 25-30% of patients Variable response: 25-30% of patients

achieve less than 25% inhibition of achieve less than 25% inhibition of platelet activityplatelet activity

Must undergo 2 step metabolism (CYP3A4 Must undergo 2 step metabolism (CYP3A4 mediated) to active agentmediated) to active agent

Binds irreversibly to P2YBinds irreversibly to P2Y1212 receptor receptor Postulated but unproven interaction with Postulated but unproven interaction with

PPIs.PPIs.Gurbel, PA, et al, Circulation 2003; 107:2908-2913;Laine L, Hennekens CH: Am J Gastro. Published online 11/13/09

Dose of Clopidogrel: Dose of Clopidogrel: CURRENT- Oasis7CURRENT- Oasis7

Randomized, double-blind, 2x2 factorial Randomized, double-blind, 2x2 factorial trialtrial

25,087 ACS patients (70.8% UA/non-25,087 ACS patients (70.8% UA/non-STEMI)STEMI)

Clopidogrel arm: double dose (600mg then Clopidogrel arm: double dose (600mg then 150mg dailyx7days then 75mg dailyx22 150mg dailyx7days then 75mg dailyx22 days) vs standard dose (300mg then 75mg days) vs standard dose (300mg then 75mg daily x29 days)daily x29 days)

Aspirin arm: 300-325mg daily vs 75-Aspirin arm: 300-325mg daily vs 75-100mg daily x 30 days.100mg daily x 30 days.

Mehta, S et al. Am Heart J. Nov 6 2008 ; 156: 1080-1088

Clopidogrel Dose ComparisonClopidogrel Dose Comparison

Overall, for efficacy, double-dose clopidogrel (600 loading dose Overall, for efficacy, double-dose clopidogrel (600 loading dose + 150 for 7 days then 75 mg for 22 days) versus standard dose ( + 150 for 7 days then 75 mg for 22 days) versus standard dose ( 300 + 75 for 29 days) produced no significant reduction in the 300 + 75 for 29 days) produced no significant reduction in the primary composite of major CV events (CV death, MI or stroke) primary composite of major CV events (CV death, MI or stroke)

The hazard ratio of 0.95 was a weighted average of 0.85 (p=.03) The hazard ratio of 0.95 was a weighted average of 0.85 (p=.03) among the subgroup undergoing PCI and 1.17 (p=0.14) among among the subgroup undergoing PCI and 1.17 (p=0.14) among the subgroup not undergoing PCIthe subgroup not undergoing PCI

Overall, for safety, using the CURRENT definitions, double dose Overall, for safety, using the CURRENT definitions, double dose clopidogrel produced significant increases in severe and major clopidogrel produced significant increases in severe and major bleeds.bleeds.

Presented at ESC Congress 2009, Barcelona Spain

ASA Dose ComparisonASA Dose Comparison

ASA 300-325 mg versus ASA 300-325 mg versus

ASA 75-100 mg showed ASA 75-100 mg showed

no significant differences no significant differences in in

efficacy or bleeding. efficacy or bleeding.

Presented at ESC Congress 2009, Barcelona Spain

Proton Pump Inhibitor and Clopidogrel Interaction Hennekens CH and DeMetsD: The need for large scale randomized evidence without

undue emphasis on small trials, their meta-analyses or subgroup analyses. JAMA, December 2, 2009. When effect sizes are small to moderate (relative risks < 1.5 – 2.0),

it is only possible to conclude whether statistical associations are valid in randomized trials with sufficient numbers of clinical endpoints and designed a priori to test the hypothesis

Bhatt D, et al The COGENT trial. Presented at TCT September 24, 2009. COGENT is the only large scale randomized trial tested

omeprazole versus placebo on CV events in clopidogrel users . This trial showed no significant difference in CV events (hazard ratio = 1.02, 95% confidence limits from 0.70 – 1.51) as well as a significant reduction in GI events (hazard ratio = 0.55, 95% confidence limits from 0.36-0.85).

Laine L and Hennekens CH. PPI and Clopidogrel Interaction: Fact or Fiction. AJG, Published online November 13, 2009. The current totality of evidence does not justify a conclusion that

PPIs are associated with clinical cardiovascular disease (CV) events among clopidogrel users, let alone support a judgment of causality.

Proton Pump Inhibitor and Clopidogrel Interaction …According to US FDA November 17, 2009

New data show that when clopidogrel and New data show that when clopidogrel and omeprazole are taken together, the omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking full effect of this medicine if they are also taking omeprazole.omeprazole.

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm

Proton Pump Inhibitor and Clopidogrel Interaction…According to Laine and Hennekens November 13, 2009

In randomized trials, PPIs seem to decrease recurrent ulcer bleeding in patients who bled on low-dose aspirin and continue aspirin. In addition, randomized, placebo-controlled trials show that both PPIs and histamine-2 receptor antagonists decrease the development of endoscopic ulcers in low-dose aspirin users. Current consensus recommendations do not specifically address clopidogrel monotherapy, but do state that patients taking dual antiplatelet therapy should receive a PPI.

Laine L and Hennekens CH. PPI and Clopidogrel Interaction: Fact or Fiction. AJG, Published online November 13, 2009.

Clopidogrel and PPI: Clopidogrel and PPI: SummarySummary

In several studies, omeprazole decreases pharmacodynamic effect of In several studies, omeprazole decreases pharmacodynamic effect of clopidogrel on surrogate markers such as platelet aggregation. Studies of clopidogrel on surrogate markers such as platelet aggregation. Studies of the other individual PPIs have not shown such effects.the other individual PPIs have not shown such effects.

Some, but not all, observational studies show that patients prescribed Some, but not all, observational studies show that patients prescribed clopidogrel have small but significant effects of all 5 PPIs on increased rates of clopidogrel have small but significant effects of all 5 PPIs on increased rates of CV events in clopidogrel users. CV events in clopidogrel users.

In one randomized trial designed to test the hypothesis, clopidogrel users In one randomized trial designed to test the hypothesis, clopidogrel users randomized to omeprazole have no increased risk of CV events.randomized to omeprazole have no increased risk of CV events.

Despite an insufficient totality of evidence, the FDA suggests that health care Despite an insufficient totality of evidence, the FDA suggests that health care providers avoid prescribing omeprazole, esomeprazole, or cimetidine to providers avoid prescribing omeprazole, esomeprazole, or cimetidine to patients receiving clopidogrel.patients receiving clopidogrel.

When the totality of evidence is incomplete it is appropriate to remain When the totality of evidence is incomplete it is appropriate to remain uncertain. uncertain.

If a healthcare provider chooses to heed the FDA then use one of the other If a healthcare provider chooses to heed the FDA then use one of the other PPIs (e.g., pantoprazole, rabeprazole) and separate the PPI and clopidogrel by PPIs (e.g., pantoprazole, rabeprazole) and separate the PPI and clopidogrel by around 14-18 hrs by prescribing the PPI before breakfast and clopidogrel at around 14-18 hrs by prescribing the PPI before breakfast and clopidogrel at bedtime or PPI at dinner and clopidogrel at lunchtimebedtime or PPI at dinner and clopidogrel at lunchtime

New Oral Antiplatelet DrugsNew Oral Antiplatelet Drugs

PrasugrelPrasugrel ThienopyridineThienopyridine More rapid onset of action More rapid onset of action

than clopidogrelthan clopidogrel Irreversible inhibitor of the Irreversible inhibitor of the

P2Y12 receptorP2Y12 receptor

Ticagrelor *Ticagrelor * Cyclo-pentyl-triazo-Cyclo-pentyl-triazo-

pyrimidine (CPTP)pyrimidine (CPTP) More rapid onset of action More rapid onset of action

than clopidogrelthan clopidogrel Reversible inhibitor of the Reversible inhibitor of the

P2Y12 receptorP2Y12 receptor

Adenosine Diphosphate-Receptor Adenosine Diphosphate-Receptor AntagonistsAntagonists

* Not approved by FDA

Triton-TIMI 38Triton-TIMI 38

13,608 patients with moderate to high-risk 13,608 patients with moderate to high-risk acute coronary syndromes with scheduled acute coronary syndromes with scheduled PCIPCI

Randomized to prasugrel (60 mg loading Randomized to prasugrel (60 mg loading dose and a 10 mg daily maintenance dose and a 10 mg daily maintenance dose) or clopidogrel (300 mg loading dose dose) or clopidogrel (300 mg loading dose and a 75 mg daily maintenance dose) for and a 75 mg daily maintenance dose) for 6-15 months. 6-15 months.

Triton –TIMI Investigators. NEJM; 357: 2001 2015

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)p=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

p=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

TRITON-TIMI 38: EFFICACY and SAFETY TRITON-TIMI 38: EFFICACY and SAFETY

CV Death / MI / Stroke

NNT = 46

NNT = 167

CV Death/MI/Stroke

TIMI Major Non-CABG Bleeds

PLATO PLATO Ticagrelor vs Clopidogrel in Patients with Ticagrelor vs Clopidogrel in Patients with

Acute Coronary SyndromesAcute Coronary Syndromes

18,624 patients with acute coronary 18,624 patients with acute coronary syndromessyndromes

Randomization: Randomization: Ticagrelor 180 mg loading dose, 90mg BID Ticagrelor 180 mg loading dose, 90mg BID Clopidogrel 300-600 mg loading dose, 75 mg Clopidogrel 300-600 mg loading dose, 75 mg

QD QD All patients received ASA 75-325 mgAll patients received ASA 75-325 mg

Wallentin, L et al NEJM 2009; 361: 1045-1057

PLATO: Time to first primary efficacy eventPLATO: Time to first primary efficacy event (CV death, MI or stroke) (CV death, MI or stroke)

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

6,743

5,096

5,161

4,047

4,147

0 60 120 180 240 300 360

1211109

876543

210

13C

um

ula

tive

inci

den

ce (

%)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

Completeness of follow-up 99.97% = 5 pts lost to follow-up

Wallentin, L Presented at ESC Congress 2009 Barcelona Spain

PLATO Time to Major Bleeding - Primary Safety PLATO Time to Major Bleeding - Primary Safety Event Event

No. at risk

Clopidogrel

Ticagrelor

9,186

9,235

7,305

7,246

6,930

6,826

6,670

Days from first IP dose

5,209

5,129

3,841

3,783

3,479

3,433

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor

11.2011.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434

K-M

est

imat

ed r

ate

(% p

er y

ear)

Completeness of follow-up 99.97% = 5 pts lost to follow-up

Wallentin, L Presented at ESC 2009 Barcelona Spain

Schӧmig, A NEJM 2009; 361: 1108-1111

Risks Associated with ADP receptorAntagonists in Patients with ACS by Trial

Issues in Clinical PracticeIssues in Clinical Practice

Unfortunately, for healthcare providers and Unfortunately, for healthcare providers and

their patients, most patients prefer the their patients, most patients prefer the

prescriptionprescription of pills to the of pills to the proscriptionproscription of of

harmful lifestyles.harmful lifestyles.

Double Cheeseburger, Large Fries, Jumbo Coffee.. Oh And An Aspirin -Gotta Take Care Of The Ticker Y’Know.

Aspirin May Reduce Risk Of Heart Attack

New Yorker Magazine. 1988.

French FriesFrench Fries

How to burn* 400 calories:

Walk 2 hour 20 minutes

20 years ago20 years ago TodayToday

210 calories

2.4 ounces How many calories are in these fries?610 calories6.9 ounces

Calorie difference: 400 Calories

*Based on 130-pound person.

Darwinism and Risk Darwinism and Risk of Cardiovascular Diseaseof Cardiovascular Disease

Walking the DogWalking the Dog

A bit of cultural news …..

After a 2 year loanto the United States, David returns to Italy…

…Proud Sponsors

Established Risk Factors for CHDEstablished Risk Factors for CHD

Blood cholesterolBlood cholesterol10% 10% = 20%-30% = 20%-30% in CHD in CHD

High blood pressureHigh blood pressure5-6 mm Hg 5-6 mm Hg = 42% = 42% in Stroke in Stroke

= 16% = 16% in CHD in CHD

Cigarette smokingCigarette smokingCessation = 50%-70% Cessation = 50%-70% in CHD in CHD

Body weightBody weight BMI<25 vs BMI>27 = 35%-55% BMI<25 vs BMI>27 = 35%-55% in CHD in CHD

Physical activityPhysical activity20-minute brisk walk daily = 35%-55% 20-minute brisk walk daily = 35%-55% in CHD in CHD

Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge, Mass: Harvard University Press; 1996.

Cancer11.9%

CVD28.4%

Communicable,Perinatal, Nutritional

34.2%

All Other25.5%

Cancer18.0%

CVD33.7%

Communicable,Perinatal, Nutritional

15.1%

All Other33.2%

Shifting Worldwide Burden of Disease

1990199019901990 2020202020202020

2005: Beijing, China vs US

Beijing US

58% Same as 1950

24.8 Same as 1990Body Mass IndexWeight in Kg/Height in m2

Cigarette smokingin men

1990 – 2010: Fast Food restaurants

in China

1990 2010

1 800 mainland200 Hong Kong

– 1,900KFC

McDonalds

Selected Worldwide Death Rates From CHD in Adults

Aged 34 to 74 Years*

*All values are for 1997.British Heart Foundation. Coronary Heart Disease Statistics: British Heart Foundation Statistics Database. London, England: British Heart Foundation; 2002.

Death Rate (per 100,000)

Country Men Women Total

Russian Federation 638 231 869

Bulgaria 353 133 486

United Kingdom 265 97 362

United States 214 87 301

Austria 223 74 297

Germany 206 72 278

France 87 20 107

Japan 57 20 77

““We must all hang together, or We must all hang together, or assuredly we shall all hang separately.”assuredly we shall all hang separately.”

– – Benjamin FranklinBenjamin FranklinJuly 4, 1776July 4, 1776

GOALS OF HEALTH CARE PROVIDERS GOALS OF HEALTH CARE PROVIDERS

AND ACADEMIC RESEARCHERSAND ACADEMIC RESEARCHERS Maximize benefit and minimize risk which is not to be Maximize benefit and minimize risk which is not to be

confused with avoidance of risk.confused with avoidance of risk.

Make clinical decisions based on the totality of evidence not Make clinical decisions based on the totality of evidence not dependence on particular subgroups of particular studies.dependence on particular subgroups of particular studies.

Avoid misstatements of benefit to risk ratios which may Avoid misstatements of benefit to risk ratios which may increase publicity, academic promotions and grant support increase publicity, academic promotions and grant support

in the short run but confuse colleagues and frighten in the short run but confuse colleagues and frighten patients and make it more difficult to conduct high quality patients and make it more difficult to conduct high quality

research research ( COX-2 inhibitors and glitazones)( COX-2 inhibitors and glitazones)

update on antiplatelet therapy in the treatment and prevention of cardiovascular disease

Documents

cvd death

aspirin20th century

national institutes

mi1988 apt shows aspirin

research grant support

national association

advisory role

large effects