Aspirin for primary prevention of CVD

ASPIRIN FOR PRIMARY
PREVENTION OF
CARDIOVASCULAR EVENTS
MODERATOR – DR. SHARAD
JAIN
PRESENTOR – DR. PINKESH
PARMAR

INTRODUCTION
Often hailed as “the wonder drug” story of aspirin dates back >3500
years when willow bark was used as a painkiller and antipyretics by
Hippocrates and other people.
Its use as antiplatelet drug started in the late 1960s and early 1970s.
Since then, role of low-dose aspirin in cardiovascular (CV) protection
has been supported by >200 studies involving >200,000 patients.

INTRODUCTION
The role of aspirin for secondary prevention of myocardial infarction
(MI), stroke, or transient ischemic attack (TIA) is well established.
However, the efficacy and safety of aspirin for primary prevention
varied among multiple randomized controlled trials (RCTs), creating
significant variability in societal guidelines.
Hence despite multiple studies, the role of aspirin for the primary
prevention remains controversial.

ASPIRIN FOR PRIMARY
PREVENTION:
THE GOLDEN PHASE
Six large randomized studies have tested the role of aspirin for the
primary prevention of CVDs since the late 1980s.

ANTITHROMBOTIC TRIALISTS
COLLABORATION
The pivotal Antithrombotic Trialists Collaboration meta-analysis
pooled individual patient data of 95,000 patients from these six
primary prevention studies.
The collaborative meta-analysis demonstrated 12% reduction in
serious vascular events with the use of aspirin which was driven
principally by 23% reduction in nonfatal MI.
There was also a 14% reduction in ischemic strokes which was
counterbalanced by increase in hemorrhagic strokes by 32%.
The net effect on strokes was not significant, while the effect on
vascular mortality was not different from placebo.
These benefits were accrued at the cost of almost 50% increase in
bleeding which were chiefly gastrointestinal (GI) and extracranial in
location.

FALLOUT OF ASPIRIN
After 2008, many negative studies came into the picture.
Two studies (POPADAD and JPAD studies) assessed effects of aspirin
in diabetes. Aspirin was not found to reduce the risk of adverse CV
events in diabetic patients in these studies.
Subsequently, aspirin was not found to reduce the risk of CV events
in those with an Ankle–Brachial Index <0.95 in The Aspirin for
Asymptomatic Atherosclerosis trial.

FALLOUT OF ASPIRIN
However, the updated systematic review of 11 randomized controlled
trials (incorporating the above trials), published by the US Preventive
Services Task Force in 2016, still revealed an impressive 22% relative
risk reduction in nonfatal MI with aspirin but only minor reduction in
nonfatal stroke, CV death, and total mortality [Figure 2].
Interestingly, elderly patients demonstrated more robust reduction in
MI.
At lower doses of aspirin (<100 mg), 14% reduction in nonfatal
strokes were seen, while reduction on MI was sustained.
However, aspirin use increased major GI bleeding risk by 58% and
hemorrhagic stroke risk by 27%.

FALLOUT OF ASPIRIN
Such conflicting results with aspirin studies have led to inconsistent
guidelines for aspirin use in primary prevention. Some societies were
in favor of aspirin use, while others were against its use.
The US. Preventive Services Task Force recommends low-dose aspirin
use for the primary prevention of CVD in adults aged 50–59 years
who have a 10% or greater 10-year CVD risk.
While in adults aged 60–69 years who have a 10% or greater 10-year
CVD risk, aspirin initiation was advised on individual basis.
Use of aspirin for the primary prevention of CVD was not endorsed by
European Guidelines due to lack of clear evidence in support of its
efficacy and increase in bleeding events.

FALLOUT OF ASPIRIN
In the background of emerging equivocal data about the role of
aspirin primary prevention, three large randomized trials involving
close to 47,000 patients were published recently.
These three trials tried to address the unresolved issues of aspirin in
primary prevention to some extent.

ASCEND TRIAL-EFFECTS OF ASPIRIN
FOR PRIMARY PREVENTION IN
PERSONS WITH DIABETES MELLITUS
Eligibility: Age ≥ 40 years, any DIABETES and no baseline
cardiovascular disease
Participants: 15,480 UK patients
Factorial randomization: Aspirin 100 mg daily vs placebo (& to
omega-3 fatty acid supplements vs placebo)
Follow-up: Mean 7.4 years, >99% complete for morbidity and
mortality
Published in NEJM on August 26, 2018

KEY OUTCOMES
Primary efficacy outcome: Serious Vascular Event (SVE)
Non-fatal myocardial infarction,
Non-haemorrhagic stroke or transient ischaemic attack, or Cardiovascular
death, excluding any intracranial haemorrhage
Primary safety outcome: Major bleed Intra-cranial haemorrhage, Sight-
threatening eye bleed,
Serious gastrointestinal bleed, or Other serious bleed
Key secondary outcomes:
SVE or any revascularization (pre-specified for subgroup analyses)
Gastrointestinal tract cancer

SUMMARY
As Aspirin did not reduce the risk of gastrointestinal or any other cancer with no
apparent effect emerging with longer follow-up
Aspirin significantly reduced the risk of serious vascular events but also significantly
increased the risk of major bleeding
The absolute benefits from avoiding serious vascular events were largely
counterbalanced by the increased risk of bleeding
There was no group in which the benefits clearly outweighed the risks

ARRIVE- USE OF ASPIRIN TO REDUCE RISK OF
INITIAL VASCULAR EVENTS IN PATIENTS AT
MODERATE RISK OF CARDIOVASCULAR
DISEASE
Published in LANCET on 26 August 2018
DESIGN - randomised, double-blind, placebo-controlled, multicentre
study done in seven countries. (Germany, Italy, Ireland, Poland, Spain,
the UK, and the USA). The study setting was largely primary care
offices.
Eligible male patients were aged 55 years and older and had between
two and four risk factors; eligible female patients were aged 60 years
or older and had three or more risk factors.
Participants had an average cardiovascular risk (10-year risk of
coronary heart disease of 10–20%), deemed to be moderate on the
basis of the risk factors.

ARRIVE
Risk factors were high cholesterol (total cholesterol >200 mg/dL or
LDL >130 mg/dL for men; total cholesterol >240 mg/dL or LDL >160
mg/dL for women) irrespective of current treatment, current smoking
(any cigarette smoking in the past 12 months), low HDL cholesterol
(<40 mg/dL), high blood pressure (systolic blood pressure >140 mm
Hg), receiving medication to treat high blood pressure, and a positive
family history of cardiovascular heart disease.
Patients were excluded if they had a history of a vascular event, such
as stroke, myocardial infarction, coronary artery angioplasty or
stenting, coronary artery bypass graft, relevant arrhythmias,
congestive heart failure, or vascular intervention.

ENDPOINTS
The primary efficacy endpoint was a composite outcome consisting of
time to first occurrence of confirmed myocardial infarction, stroke,
cardiovascular death, unstable angina, or transient ischaemic attack.
Secondary endpoints were a composite of the time to first occurrence
of cardiovascular death, myocardial infarction, or stroke; time to
individual components of this composite secondary outcome; time to
first occurrence of unstable angina; time to first occurrence of
transient ischaemic attack; and time to and incidence of all-cause
mortality.
Safety endpoints were haemorrhagic events and incidence of other
adverse events,

RESULTS
Between July 5, 2007, and Nov 15, 2016, 12 546 patients were
enrolled and randomly assigned to receive aspirin (n=6270) or
placebo (n=6276) at 501 study sites. Median follow-up was 60
months.

ASPREE-EFFECT OF ASPIRIN ON ALL-
CAUSE MORTALITY
IN THE HEALTHY ELDERLY
Published in NEJM 16 September 2018
Randomized Multi-center placebo controlled Trial With Multi YearFollow-
up
ASPREE trial was a primary prevention trial that was established to
investigate whether the daily use of 100 mg of enteric-coated aspirin
would prolong the healthy life span of older adults.
The trial, which was conducted in Australia and the United States,
recruited 19,114 relatively healthy older persons from community
settings.

ASPREE
From 2010 through 2014, they enrolled community-dwelling persons
in Australia and the United States who were 70 years of age or older
(or ≥65 years of age among blacks and Hispanics in the United
States) and did not have cardiovascular disease, dementia, or
disability. Participants were randomly assigned to receive 100 mg of
enteric-coated aspirin or placebo.
Followed Patients until Death/Disability Median 4.7yrs

SUMMARY
Aspirin has a beneficial profile for reducing nonfatal MI but not all cause or CV
mortality in general
Primary prophylaxis is not likely to result in decreased cardiovascular mortality, or
all cause mortality/disability
Aspirin use is significantly associated with serious hemorrhage
All-cause mortality was apparently higher among those who received
daily low-dose aspirin than among those who received placebo, with
1.6 excess deaths per 1000 person-years occurring in the aspirin
group after a median of 4.7 years, and cancer was the principal cause
of the excess deaths. Other primary prevention trials of aspirin have
not identified similar results, which suggests that the mortality
results reported here should be interpreted with caution.

These three studies used contemporary pharmacotherapy in the
management of CVD. With large sample size and close to half-decade
follow-up in these studies, the results would be hard to neglect.
One can only speculate about the various possible reasons for
contrasting results seen in the pristine trials.
The initial aspirin trials occurred in an era when other risk factors of
vascular diseases were not well controlled such as blood pressure and
lipid profile. With development of statins, renin–angiotensin–
aldosterone system blockers, and better management of CV risk
factors, event rates are already on decline.

ASPIRIN FOR PRIMARY
PREVENTION OF
CARDIOVASCULAR EVENTS – A
META-ANALYSISPublished by Abdelaziz et al. in JACC VOL .73, on JUNE 18, 2019
Randomized controlled trials comparing clinical outcomes with
aspirin versus control for primary prevention with follow-up duration
of >1 year were included.
A total of 15 randomized controlled trials including 165,502
participants (aspirin n = 83,529, control n = 81,973) were available
for analysis.
The current meta-analysis represents the largest and most
contemporary examination of long-term outcomes with aspirin use
for primary prevention of CVD.

Efficacy outcomes included all-cause death, cardiovascular (CV)
death, myocardial infarction (MI), stroke, transient ischemic attack
(TIA), and major adverse cardiovascular events.
Safety outcomes included major bleeding, intracranial bleeding, fatal
bleeding, and major gastrointestinal (GI) bleeding.

Primary analysis found that:
1) aspirin is not associated with a reduction in all-cause or non-CV death,
but is associated with a modest, nonstatistically significant relative
reduction of 7% in CV death;
2) aspirin (even <100 mg/day) is associated with lower rates of MI,
nonfatal MI, TIA, and ischemic stroke;
3) aspirin use is associated with a significant increase in the risk of
nonfatal major bleeding events, intracranial bleeding, and major GI
bleeding, with similar rates of fatal bleeding compared with the control
subjects regardless of dose or population characteristics; and
4) aspirin does not affect the incidence of cancer or risk of cancer death
within a median follow-up period of 6.46 years.

Secondary analysis revealed that:
1) aspirin may reduce all cause death after 5 years of follow-up;
2) the trend toward lower risk of CV death with aspirin is only
observed in populations with high estimated 10-year ASCVD risk;
and
3) lower risk of total and nonfatal stroke with aspirin use is observed
only when lowdose aspirin (<100 mg/day) is utilized.

1. LOW-DOSE ASPIRIN (75-100 MG ORALLY DAILY) MIGHT BE
CONSIDERED FOR PRIMARY PREVENTION OF ASCVD AMONG SELECT
ADULTS 40 TO 70 YEARS OF AGE WH ARE AT HIGHER ASCVD RISK BUT
NOT AT INCREASED BLEEDING RISK
To balance the benefits and risks, prior U.S. guidelines have
recommended prophylactic aspirin only in the setting of elevated
ASCVD risk.
In this context, post hoc study of older trials suggests that the
benefit–risk ratio for prophylactic aspirin generally becomes more
favorable at >10% estimated 10-year ASCVD risk.
However, the relative benefits of aspirin, specifically in preventing
nonfatal MI and perhaps stroke (with a trend to lower mortality) have
been less evident in more recent trials.

1. LOW-DOSE ASPIRIN (75-100 MG ORALLY DAILY) MIGHT BE
CONSIDERED FO THE
PRIMARY PREVENTION OF ASCVD AMONG SELECT ADULTS 40 TO 70
YEARS OF AGE WHO ARE AT HIGHER ASCVD RISK BUT NOT AT
INCREASED BLEEDING RISK
Recent trials show that absolute risk for ASCVD events typically
exceeds that of bleeding and, although the gap of relative benefit to
relative harm for aspirin has narrowed, the number needed to treat to
prevent an ASCVD event remains lower than the number needed to
harm to cause bleeding.
meta-analyses suggest that the ASCVD risk benefit for low-dose
aspirin is equivalent to that for high-dose aspirin, but the bleeding
risk is higher with high-dose aspirin.
there was no evidence low-dose aspirin was any more effective in
low-weight individuals than in high-weight individuals in the more
recently published ASCEND (A Study of Cardiovascular Events iN
Diabetes) trial.

2. LOW-DOSE ASPIRIN (75-100 MG ORALLY DAILY) SHOULD NOT BE
ADMINISTERED ON ROUTINE BASIS FOR THE PRIMARY PREVENTION
OF ASCVD AMONG ADULTS >70 YEARS OF AGE
Prophylactic aspirin in primary-prevention adults >70 years of age is
potentially harmful and, given the higher risk of bleeding in this age
group, difficult to justify for routine use.
In addition, for adults <40 years of age, there is insufficient evidence
to judge the risk–benefit ratio of routine aspirin for the primary
prevention of ASCVD.
As inferred from the first recommendation, there is also no
justification for the routine administration of low-dose aspirin for the
primary prevention of ASCVD among adults at low estimated ASCVD
risk.

3. LOW-DOSE ASPIRIN (75-100 MG ORALLY DAILY) SHOULD NOT BE
ADMINISTERED FOR THE PRIMARY PREVENTION OF ASCVD AMONG
ADULTS OF ANY AGE WHO ARE AT INCREASED RISK OF BLEEDING
The accumulated trial and observational data to date support
avoiding prophylactic aspirin in the setting of known risk factors for
increased bleeding outcomes.
A nonexhaustive list of scenarios associated with increased risk of
bleeding includes: a history of previous gastrointestinal bleeding or
peptic ulcer disease or bleeding from other sites, age >70 years,
thrombocytopenia, coagulopathy, CKD, and concurrent use of other
medications that increase bleeding risk, such as nonsteroidal anti-
inflammatory drugs, steroids, direct oral anticoagulants, and
warfarin.

CONCLUSIONS
Aspirin use for primary prevention decreased nonfatal ischemic
events and increased nonfatal bleeding events.
The benefits were more pronounced when estimated ASCVD risk was
>7.5% over 10 years.
These findings suggest that the decision to use aspirin for primary
prevention should be tailored to the individual patient based on
estimated ASCVD risk and perceived bleeding risk, as well as patient
preferences regarding types of events prevented versus potential
bleeding caused.
When aspirin is used for primary prevention, a low dose (<100
mg/day) should be recommended.

INTRODUCTION
Despite the development of new molecules, aspirin remains a
mainstay of the antiplatelet therapy, indispensable for treatment and
the secondary prevention of cardiovascular and cerebrovascular
diseases.
A significant number of these patients manifest breakthrough events
despite regular intake of aspirin.
It is estimated that one in eight high risk patients suffers from the
recurrence of a vascular event within the next 2 years.

MECHANISMS OF ACTION OF ASPIRIN
Aspirin mediates its antithrombotic effect through inhibition of
platelet aggregation. It does this by inhibition of cyclooxygenase-1
(COX-1) which in turn inhibits the metabolism of arachidonic acid to
cyclic prostanoids such as thromboxane A2, prostacycline and other
prostaglandins.
Because platelets have minimal capacity for protein synthesis, the
inactivation of COX-1 by aspirin is irreversible for the life of the
platelet (8-10 days)

DEFINITION OF ASPIRIN
RESISTANCE
Aspirin resistance is a poorly defined term.
It could mean a clinical inability of aspirin to protect individuals from
arterial thrombotic events or laboratory indication of failure of aspirin
to inhibit platelet activity, mainly platelet aggregation or a close to
normal urinary concentration of thromboxane metabolites.

PREVALENCE OF ASPIRIN RESISTANCE
There are no standard criteria or method by which aspirin resistance
can be assessed.
Aspirin resistance has been reported to occur in 5% to 45% of the
general population

METHODS OF ASSESSING ASPIRIN RESISTANCE
1) Platelet aggregation studies using platelet rich plasma (optical
aggregometer) or whole blood (platelet function analyzer-100;
PFA-100) are the usually employed method. Optical aggregometer
is widely available, however it is neither reproducible nor user-
friendly. Whereas whole blood aggregometer allows more rapid
assessment and results are easily reproducible. Other method
used is rapid platelet function analysis (RPFA) using Ultegra RPFA
instrument.
2) Bleeding time
3) Urinary metabolites of thromboxane metabolism- urinary 11-
dehdrothromboxane B2 levels, a stable metabolite of TXA2. As the
urinary levels depend on platelet and nonplatelet sources of
thromboxane generation, this test lacks specificity.

Criteria used for the diagnosis of aspirin resistance also varies among
different authors.
Using platelet aggregation Gum et al defined resistance as
aggregation of >70% with 10μm ADP and >20% with 0.5mg/ml
arachidonic acid.
Aspirin semiresponder was defined as meeting one criteria but not
both.
With PFA-100 aspirin resistance was defined in terms of normal
collagen and/or epinephrine closure time <186 sec and with RPFA-
as aspirin resistance units >550.

MECHANISMS OF ASPIRIN RESISTANCE
CLINICAL
Non-compliance
Drug interaction: Most important is with ibuprofen. Ibuprofen is able
to bind the COX-1 binding site of aspirin and via stearic hindrance
may prevent aspirin from binding and exerting its antiplatelet effect
Cigarette smoking enhances platelet function.
Diabetes and hypercholesterolemia – by means of producing free
radicals decreases response to antiplatelet therapy.

BIOLOGIC/ CELLULAR FACTORS
Alternate pathways of platelet activation.
Failure to inhibit catecholamine-mediated platelet activation e.g.
exercise, mental stress, epinephrine.
Overexpression of COX-2 mRNA
Regenerated COX-1 activity in macrophages and vascular endothelial
cells
Erythrocyte-induced platelet activation
Generation of B2-isoPGF2 alpha binds to thromboxane receptors

GENETIC
Polymorphism of vWF receptor gene
Polymorphism collagen receptor
Functional single nucleotide polymorphism of COX-1 gene
Platelet glycoprotein IIIa polymorphism. The platelet glycoprotein
IIb/IIIa complex is the receptor for fibrinogen and mediates platelet
aggregation. Polymorphism exists in the IIIa subunit of this receptor
with patients being PI A1/A1 homozygous, Pl A1/A2 heterozygous or
Pl A2/A2 homozygous. Patients displaying either the Pl A1/A2 or Pl
A2/A2 polymorphism have been shown to be less responsive to the
antiplatelet effect of aspirin. But, the main cause for aspirin
resistance may be a yet undiscribed genetic abnormality.

TYPES OF ASPIRIN RESISTANCE
1. Aspirin resistance type I (pharmacokinetic type) – There is no
effect on collagen-induced platelet aggregation or thromboxane
formation while taking aspirin 100 mg/da for at least 5 days.
While there is inhibition of platelet aggregation in vitro suggesting
intra- and inter-individual variability in pharmacokinetics when
aspirin is used at low doses.
2. Aspirin resistance type II (pharmacodynamic type) - It is
characterized by the inability of aspirin to inhibit platelet
thromboxane formation both in vivo and in vitro.
3. Aspirin resistance type III (pseudo-resistance) - It is characterized
by inhibition of thromboxane formation in vivo but not in vitro.
This type of aspirin resistance was designated ‘pseudo-
resistance’, because, in these patients, aspirin exerted the
expected pharmacodynamic effect, i.e., inhibition of platelet
thromboxane formation.

MANAGEMENT OF ASPIRIN RESISTANCE
There are no specific recommendations regarding the management of
aspirin resistance.
General measures- Patient compliance
Increasing aspirin dose- Data from Clopidogrel in Unstable angina to
prevent Recurrent Events (CURE) and Blockage of the Glycoprotein
IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) studies show
that increasing aspirin dose is not useful.

MANAGEMENT OF ASPIRIN RESISTANCE
Combining with other antiplatelet agents-Clopidogrel inhibits platelet
aggregation via ADP receptor and therefore may represent an
important therapeutic alternative. trial Clopidogrel versus Aspirin in
Patients at Risk of Ischemic Events (CAPRIE)) has shown a modest
superiority of clopidogrel monotherapy over aspirin monotherapy.
Both CURE and Clopidogrel for the Reduction of Events During
Observation (CREDO) support the superiority of dual antiplatelet
therapy over monotherapy. However resistance to other antiplatelet
agents has also been reported. In a recent study up to 4.7% of the
patients undergoing coronary stenting developed thrombotic stent
occlusion despite intensive clopidogrel treatment.

Aspirin for primary prevention of CVD

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