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Aspirin in primary prevention: lights, shadows, and areas of uncertainty

Sergio Coccheri University of Bologna - Italy

5th Joint Advanced Educational Course of ISTH and MLTD

“Thrombosis and antithrombotic therapy in cardiovascular disorders�

Kiev, April 4-5 2013

The spectrum of cardiovascular risk

Risk of a major cardiovascular event: death, myocardial infarction, stroke (n. of events/100 subjects/year) Normal subjects (any age) = <2

High-risk primary prevention = 2-4

Post-MI (chronic phase) , poststroke, and stable CAD = >4

ACS= >10

PRIMARY versus SECONDARY PREVENTIOIN  From three large metanalyses of secondary prevention (BMJ 1994; BMJ 2002; Lancet 2009) it can be inferred that aspirin reduces the RR of major CV events by about 30% (EFFICACY)  Even assuming a similar EFFICACY also in primary prevention, the much lower absolute number of events occurring will translate into lower EFFICIENCY, and higher NNT (a useful virtual figure) De Caterina , Coccheri et al, G Ital Card 2012

EFFICACY and EFFICIENCY of aspirin at different levels of CV risk in secondary and primary prevention CV risk level No. events % pts/year

Relative RR

Absolute RR (No. Events)

NNT

ACS (high risk)

15

- 30%

4.5

22.2

Stable angina (medium risk)

4

- 30%

1.2

83

Primary prevention (low risk)

1

-30% (?)

0.30

333

Condition

De Caterina , Coccheri et al, G Ital Card 2012 Nota: However, as primary prevention could be extended to whole populations, the small absolute reduction could translate into exceedingly high numbers.

Synopsis of 4 recent meta-analyses of trials of primary CV prevention with aspirin Berger JS et al. Bartolucci AA et al Raju N et al 2011 2011 2011 RR OR RR

Seshasai SRK et al 2012 OR

Non fatal MI

0.84 n

0.81*

0.83*

0.80*

Stroke (all)

0.94 n

0.92 n

0.93 n

0.94 n

Composite endpoint째

0.90*

0.86*

0.88*

0.90*

Vascular mortality

0.99 n

0.96 n

0.96 n

0.99 n

Total mortality

0.94 n

0.94 n

0.94 n

0.94 n

째Composite endpoint= nf MI + nf Stroke + Vasc Death; *= significant; n= no significant Comment Across the 4 meta-analyses, there is total concordance on Composite Endpoint (always significant). Quasi-accord in non-fatal AMI (sig 3 on 4). Negative total concordance for vascular and total mortality (claimed significant by Raju).

NET BENEFIT OF ASPIRIN IN PRIMARY PREVENTION But!  The net absolute benefit versus risk for aspirin in primary prevention results to be very limited or null  On 1000 persons treated for 5 years there were:  About 3 ischemic events avoided  About 3 major bleedings caused

that makes a poor net benefit From Berger JS, Am Herat J, 2011

The net benefit in primary prevention may increase only in persons with global cardiovascular risk greater than 2 events%/pts/year

Eur Heart J 2012;33:1635-1701

The diabetes paradox (I) • Aspirin is validated in secondary prevention of CV events in diabetes • Diabetes is a coronary heart disease equivalent (?)

• …Then aspirin should be also effective in diabetes without CV complications • But …. this is not the case….!

PRIMARY AND SECONDARY PREVENTION WITH ASPIRIN ON MORTALITY AND CV EVENTS IN PEOPLE WITH DIABETES A meta-analysis • 20 studies including 17,522 pts of which 13 of secondary prevention and 7 on primary prevention • Aspirin use in secondary prevention associated with lower mortality RR= 0.82; p = 0.03 • Aspirin use in primary prevention was not RR= 1.01; n.s.

• Results regarding cardiovascular events were highly heterogeneous among trials Simpson SH et al. J Gen Int Med 2011

Association of Aspirin Use With Major Bleeding in Patients With and Without Diabetes - a prospective cohort study -

In a large cohort of users of low dose aspirin (median follow-up 5.7y), incidence of major bleeding (GI + IC) was 5.6 per 1000 persons/year versus 3.6 in non users, excess due to aspirin 2 events x 1000 persons year.

Diabetes was a risk factor for major bleeding (IRR 1.36) but aspirin did not increase the bleeding risk in diabetics.

Modified by G. De Berardis et al. JAMA.2012.

Baseline Cardiovascular Risk (for CAD) and cardiovascular event rates in asymptomatic patients with diabetes. The DIAD study I On 1123 pts with DM, follow-up 5y Low Risk

(+)

(<10%)

Interm. Risk

(+)

High Risk

(10-20%)

(>20%)

Framingham score

25%

(73%)

48%

(74%)

UKPDS Risk engine

47%

(87%)

40%

(53%)

Primary CVE

1,3%

2,6%

27% 13% 7,3%

from Bansal S et al , Diabetes Care 2010 - adapted

Guidelines for Primary Prevention of CV events in Diabetes

Low-dose (75-162 mg/d) aspirin for primary CV prevention in diabetics is â&#x20AC;&#x153;reasonableâ&#x20AC;? for adults at increased CV risk: 10 y risk = 10% or more (Class Iia, evidence B-C).

Thus, males over 50 and females over 60, with one or more major risk factors (smoke, HBP, lipids, familial premature CVD, albuminuria) are included

Pignone et al. AHA-ADA Guidelines Circulation 2010

FROM VASCULAR TO TOTAL MORTALITY The role of cancer mortality

 It can be observed that vascular mortality across the 4 meta-analises is little reduced and never significantly  Whereas total mortality is more evidently and consantly reduced (0.94), approaching significance (see Raju)  The reason for this discrepancy could be an effect of aspirin on non-vascular, and especially on cancer mortality

Effect of aspirin at any dose (75 to 650 mg) on cancer mortality (I) studies of primary or secondary CV prevention -Long term effects A meta-analysis of 7 trials with individual data • Trials had mean or median duration of 4 y, range >5y • Benefit apparent only after 5y follow-up GENERAL RESULTS All cancers: Digestive cancers:

ASA vs CONTROLS HR 0.66 (0.50-0.87) HR 0.46 (0.27-0.77)

p= 0.03 p= 0.03

All solid cancers: Digestive cancers:

HR 0.80 (0.72-0.88) HR 0.65 (0.54-0.78)

p < 0.0001 p < 0.0001

Influencing factors:

long term treatment duration (≥ 7.5y); elderly age; any dose of aspirin Rothwell PM et al. Lancet 2011

20y RISK (three trials)

Effect of aspirin on cancer incidence and mortality (II) Short term effects From an analysis of 51 randomized trials  In six trials of primary CV prevention low dose aspirin reduced cancer incidence from 3y onwards in men and women (OR 0.76/0.77, p significant)  With increasing follow up effect on CVE and bleedings declined leaving alone the reduced risk of cancers  The absolute reduction in cancer incidence was 3.13 cases per 1000 pts/year from 3y onwards Rothwell PM et al. Lancet 2012

Low-dose aspirin and cancer mortality (III)  A meta-analysis of 23 randomized trials of low dose aspirin, primary or secondary prevention, any duration  All trials reported non-vascular mortality that was reduced by aspirin: RR 0.88 (0.81-0.96)  11 trials reported on cancer reduced: RR 0.77 (0.63-0.95)

mortality that was more

 Effects became statistically significant after 4y follow up

Mills EJ et al. Am J Med 2012

From “primary” to “secondary” prevention: no dicotomy, rather a continuum - Apparently healthy person (consider also gender, age, etc) - Presence of classic risk factors (global CV risk ≥2/100 pts/y) - For borderline values of global CV risk, consider to incorporate when appropriate: - Diabetes, metabolic syndrome, obesity - Hypertension - Asymptomatic ATS plaque (carotid, renal) (+ IMT?) - Ankle-brachial index (asymptomatic PAD) - Left ventricular hypertrophy - Coronary calcium score - Creatinine clearance and micro, macro albuminuria - Previous unprovoked DVT (?) (Aspirin for dual prevention) - Familiarity (or PIK 3CA mutation) for colo-rectal cancer ( H.R. with ASA for mortality reduction by ca 0.18, by all cause 0.54. Liao X et al, NEJM 2012)

Our recommendations …(in partial disagreement with the 2012 ESC Guidelines on CVD prevention) Especially considering the absolute figures of benefit (CV events avoided) and harm (major bleedings related to aspirin) we recommend to limit primary CV prevention with aspirin in “healthy” subjects with no previous CV events, to those with an estimated global cardiovascular risk ≥ 2 major CV events per 100 pts/year (Progetto Cuore).

This cut-off should also be adopted for primary prevention in patients with type 2 diabetes.

De Caterina R, Coccheri S. G Ital Cardiol 2012

FINAL CONSIDERATIONS (I)  In primary CV prevention, we propose to reserve treatment with low dose aspirin to healthy persons with a global cardiovascular risk higher than 2 events on 100 pts/year.  In this way a net benefit of CV events versus bleeding will be obtained  We can expect essentially a reduction of non-fatal MI but not of stroke nor of vascular mortality, both in diabetic and non diabetic subjects  We can also expect a reduction (non-significant) in all-cause mortality essentially driven by a significant lowering of cancer mortality: especially but not only for colo-rectal cancer

FINAL CONSIDERATIONS (II)  At long term, the effect on cancer mortality will be prevalent even after discontinuation of treatment  It is difficult to compare the cardiovascular and the anti-cancer effects of aspirin because the latter effect is different in onset, timing, progression and persistence after end treatment and includes efficacy also on incidence and metastatization of malignancies  For the time being, it seems appropriate to consider at least the risk of colo-rectal cancer as an adjunctive factor for the indication of a primary low dose aspirin prophylaxis

RESISTANCE TO ASPIRIN IN TYPE 2 DIABETES MELLITUS • High prevalence of “ex-vivo” aspirin resistance correlated to glycation of Hb or other proteins (Watala C et al. Thromb Res 2004, J Mol Med 2005; Di Minno G et al. Thromb Res 2004) • Increased platelet turnover • Activation of ASA insensitive COX2 • Increased thromboxane production by extraplatelet sources • Platelet aggregation due to free radicals, or lypoxigenase products as isoprostanes • Thrombin induced platelets aggregation (Coccheri S., Drugs 2007)

Recent International Guidelines for Antithrombotic Therapy (primary prevention) Recommendation 2..1 For persons aged 50 years or older without symptomatic cardiovascular disease we suggest lowdose aspirin 75 to 100 mg daily, over no aspirin therapy (Grade 2B) But, in the remarks: â&#x20AC;&#x153;In people at moderate to high risk of CV events the reduction in AMI is closely balanced with an increase in major bleedsâ&#x20AC;?.

ACCP Guidelines. CHEST 2012

A meta-analysis of individual participant trials: ASA in primary prevention of CV events and death

Endpoints considered are not significant except for nf AMI (especially in males)

ATT Coll. Lancet 2009

Observations on the bleeding risk • The patient or his doctor may “prefer” a reduction of the CV risk and “accept” an increase of bleeding risk, as judged liable to better control.

• However, bleedings may need transfusion; digestive bleedings can worsen cardiovascular risk; discontinuation of aspirin may be followed by CV events etc. (Derogar et al, Clin Gastroenterol Hepatol, 2011) • There is therefore need of caution in excessively extending the use of aspirin in primary prevention.

A recent Metanalysis of Trials of ASA in DM with no CV complications

A= effect of aspirin on risk of Stroke RR 0.91 B= effect of aspirin on risk of AMI RR 0.85 Both effects non significant

Pignone M et al. JACC 2010

The diabetes paradox (II) • In ACS (secondary prevention) diabetes is a condition maximizing the benefit of a single or dual antiplatelet therapy • … and yet in diabetes without a vascular event, even on top of asymptomatic peripheral arterial disease, no clear benefit of aspirin even against placebo is apparent

Volpe M et al. J Hypert 2012

Primary prevention with aspirin in absolute values â&#x20AC;&#x153;The pooled results found a statistically significant 10% relative reduction in major cardiovascular events (MACE) and a significant relative increase in major bleeding events of 62%.

In absolute terms, in 1000 patients treated over 5y, this will translate into 3 ischemic events avoided at the price of 3 major bleedingsâ&#x20AC;?

(Berger JS et al. Ann Heart J, 2011) Then, what should be done?

Practice primary CV presentation with aspirin in healthy subjects that have a global risk of CV events > 2 CV events % pts/year.

In fact, efficacy of aspirin is constant at any risk level (Baigent 2009) but in presence of more events, efficiency of aspirin will be higher (De Caterina, Coccheri et al, 2012)

Aspirin for primary prevention of cardiovascular events: the North American view EVIDENCES: aspirin (low dose) reduces CV events in patients without known history of CVD: specifically AMI in men, ischemic stroke in women. No effect on mortality in either gender. Aspirin increases major and digestive bleedings in both genders and intracranial in men.

(Wolff T et al. Ann Int Med, 2009) RECOMMENDATION Use of aspirin for primary prevention is â&#x20AC;&#x153;encouragedâ&#x20AC;? in men 45-75 and women 55-79 years when potential benefit of a reduction of the above events outweighs the potential harm of digestive hemorrhage.

(US Preventive Service Task Force Ann Int Med, 2009)

Beware of commonly quoted statements!

10-y cumulative risk of major cardiovascular events in various contemporary studies Secondary prevention COURAGE, 2007

Follow-up, y

Risk of major CV event

Projected 10-y risk

4,60

18,50

40,2

*=not including stroke

15,3 26,9

*=including amputation *=including amputation

Primary prevention - high risk (diabetes ± PAD) JPAD, 2009 POPADAD, 2009

4,37

6,70

6,70

18,00

• Diabetes per se is NOT always a coronary heart disease equivalent!

• It is not a CHD equivalent in contemporary trials

ATT COLLABORATION 2009 Individual data meta-analysis – Primary Prevention THE RISK FACTOR PARADOX Rate Ratios

Data from ATT Collaboration, Lancet 2009

DIABETES

Yes 0.88 No 0.87

HYPERTENSION

Yes 0.87 No 0.88

CHOLESTEROL µmol/l

≥6 <6

GLOBAL CV RISK per 100/10y

> 10 0.89-1.07 < 10 0.82-0.87

BMI

> 30 0.84 < 25 0.85

SMOKING

Yes 1.00 No 0.83

0.82 0.85

Is there a rationale for prescribing Aspirin in primary prevention according to the level of risk factors or of the global risk?

The DIAD study II On 1123 pts with DM, follow-up 5y Comments:

• Patients with type 2 DM are highly inhomogeneous in regard to CV risk • Actual event rates are consistently lower than predicted rates • UKPDS score is the best predictor of actual CV events, especially in Pts with high estimated risk from Bansal S et al , Diabetes Care 2010 - adapted

Antiplatelet Therapy in Patients with Diabetes 1. There is currently no evidence to recommend routine use of ASA at any dose for the primary prevention of vascular ischemic events in patients with diabetes (Class III, Level A).

2. For patients with diabetes aged more than 40 years and at low risk for major bleeding, low-dose ASA (75-162 mg daily) may be considered for primary prevention in patients with other cardiovascular risk factors for which its benefits are established (Class IIb, Level B).

3. Low-dose ASA therapy (75-162 mg daily) may be considered for secondary prevention in patients with diabetes and manifest vascular disease for which its benefits are established (Class I, Level A).

4. Clopidogrel 75 mg daily may be considered for secondary prevention in patients with diabetes who are unable to tolerate ASA (Class IIa, Level B).

Kraw ME, Rabasa-Lhoret R, Canadian Cardiovascular Society Guidelines 2010

CONCLUSION (I) • Aspirin has a modest effect in primary prevention, and should be prescribed only on an individual basis • Aspirin is also little effective especially in primary, but probably also in secondary prevention of cardiovascular events in subjects with type 2 diabetes mellitus, despite the higher CV risk of this population • At any rate, the risk of diabetes “per se” is not equivalent to that of CHD • A high prevalence of “poor responders” to aspirin and to clopidogrel has been found among diabetics, both in acute (ACS) and in chronic settings

ASPIRIN FOR CARDIOVASCULAR PREVENTION IN PTS WITH DIABETES AND NO CARDIOVASCULAR DISEASE A METANALYSIS • Six of 157 studies eligible with > 10,000 pts (1966-2008) • Major composite CV events (5 studies) RR 0.99 (ns) • Cardiovascular mortality (4 studies) RR 0.94 (ns) • All-cause mortality (4 studies) RR 0.93 (ns) • Myocardial infarction RR 0.57 (sig) in men; 1.08 (ns) in women De Berardis G et al BMJ 2009

• Bleeding due to aspirin is increased by 95% in diabetics Pignone M et al. JACC 2010

ASPIRIN FOR PRIMARY PREVENTION OF CV EVENTS IN PEOPLE WITH DIABETES The June 2010 statements of ADA, AHA, ACC  Aspirin has a modest effect in this setting (RRR ~ 10%). Subjects at higher risk will have an increased absolute benefit but also may have higher rates of bleeding  Low dose ASA reasonable for adults with DM with a risk of CVE over 10% in 10 years if not at increased bleeding risk. Mostly, they are men > 50 and women > 60 with one or more major RF as: smoking, HBP, dyslipidemia, albuminuria, familiarity for early CVD  Low dose ASA considered for subjects at intermediate CVD risk (5-10%) or younger people with RF, or older with no RF  Low dose ASA not recommended if CVD risk < 5% in 10 years (young age, no RF) Pignone M et al, Circulation 2010

Bleeding risk of combined antiplatelet treatment.

Odds ratio for severe upper digestive bleeding Among 1443 cases of severe upper digestive bleeding observed in Funen County, DK, between 2000 and 2004, association with AP drugs gave following OR: ODDS RATIOS FOR BLEEDING Agent(s) OR _______________________________ ASA l.d.

1.8 CLOP 1.1 DYP 1.9 AVK 5.3 CLOP/ASA 7.4 AVK/ASA 5.3 DYP/ASA 2.3

No of treatment years to induce 1 excess case: CLOP alone 8800 CLOP / ASA 124

Hallas J et al. BMJ 2006