Body Weight Adjusted Clopidogrel treatment in patients with CORonary artery Disease (BW-ACCORD)

Dual antiplatelet therapy (DAPT), consisting of aspirin combined with a
P2Y12-inhibitor (preferably clopidogrel), is the standard treatment for
patients with chronic coronary syndrome (CCS) treated with percutaneous
coronary intervention (PCI) according to European guidelines (class I) to
prevent recurrent ischemic events. In patients with acute coronary syndrome
(ACS) and any contra-indication for ticagrelor/prasugrel or a high bleeding
risk, de-escalation from ticagrelor/prasugrel to clopidogrel, blind or by the
use of CYP2C19 genotyping or platelet function testing is optional.

In CCS patients the 2017 focused update on dual antiplatelet therapy ESC
guideline recommends DAPT for 6 months, which can be shortened based on the
bleeding risk. The trade-off of thrombotic prevention by DAPT is an increased
incidence of bleeding, while major bleeding is associated with an increase in
mortality. With the recent developments of better stents with less
stent-thrombosis, new strategies to reduce bleeding and optimize treatment are
being explored.

Extreme body weights (BW) or body mass index (BMI) affect the pharmacokinetics
of antithrombotic drugs and consequently may affect cardiovascular risk during
treatment. As a consequence the ESC Working group on Thrombosis has addressed
the following as a pending issue: *Determining whether the benefit: risk ratio
of oral fixed-dose antiplatelet and anticoagulant drugs can be improved using a
BW and/or BMI dose adjustment**.
Standard therapeutic regimens and dosing of antithrombotic drugs are largely
based on patients with normal-overweight or class 1 obesity. Therefore,
fixed-dose drugs might be over- or under-dosed in severely underweight or
severely obese patients. This has the potential of impacting the bleeding and
thrombosis balance of each drug regimen, considering also the
bodyweight-associated thrombotic and bleeding risk, independently of
antithrombotic drug use.
Several studies have reported poor responsiveness to clopidogrel, expressed as
reduced platelet inhibition and/or active metabolite concentration, associated
with a high BMI or BW. On the contrary, (extreme) low BW has been associated to
a higher bleeding risk.

As high BW is associated with an increased risk for coronary artery disease
(CAD), there are proportionally more overweight than underweight patients in
the CAD population. As a result, there is little data on underweight patients
and cardiovascular risk, (on-treatment) platelet activity and risk of
cardiovascular events, such as bleeding and recurrent atherothrombotic events.
A large single-center prospective cohort study with 9738 Dutch patients at risk
for cardiovascular disease (due to risk factors or symptomatic arterial
disease), showed that the patients with the lowest BMI (BMI 15.90-23.94) had
the highest risk of bleeding. In a smaller observational study (N = 774) low
BMI (< 18.5) was associated with deep intracranial bleeding risk (OR = 1.76, p
= 0.011). In patients undergoing PCI, a low BMI (BMI <18.5) increased risk the
risk of bleeding, while class 1-2 obesity has a reduced risk. Both minor and
major bleeding appeared to be most prevalent in the low BMI group.

Explained both by pathophysiological as by clinical observations, a high BMI is
associated with a higher risk on cardiovascular disease and mortality. In
obesity adipose tissue consists of adipocytes and different cell types in the
vascular stroma. During weight gain, adipocytes become hypertrophic, hypoxic
and dysfunctional, releasing pro-inflammatory molecules that attract
pro-inflammatory cells (neutrophils, CD8 T cells, B cells, mast cells, and
interferon-c-Th1). Moreover, obesity increases lipid peroxidation and
isoprostane formation, which can activate platelets. Consequently, a state of
low-grade chronic inflammation can develop, which by impaired fibrinolysis and
endothelial dysfunction can lead to hypercoagulability and platelet activation,
ultimately resulting in a higher thrombotic risk. In the clinical practice a
high BMI is associated with venous thromboembolism, a higher frequency of
plaque rupture in coronary atherosclerosis and higher cardiovascular mortality.
In the LEADERS trial, BMI independently predicted major adverse cardiac events
at 1-year in patients on clopidogrel 75mg daily.

Clopidogrel therapy and BMI/BW
As stated earlier, previous research has shown that the response to
clopidogrel, assessed by platelet inhibition or active metabolite concentration
can be influenced by extreme weights. Angiolillo et al. showed that suboptimal
platelet aggregation inhibition was significantly higher in overweight than in
normal weight patients at baseline, at 24 hours and during the overall study
time. An elevated BMI was the only independent predictor of suboptimal platelet
response.
In a study by Bonello-Palot et al. clopidogrel dose adjustments were made to
overcome high on-treatment platelet reactivity (HTPR) in patients after PCI.
Though also influenced by the CYP2C19 gene allel, the only independent
predictor of a failed dose adjustment was a high BMI. Pankert et al. analyzed
the platelet reactivity in post-PCI patients treated with clopidogrel (both
75mg and 150mg) and prasugrel (10mg). HTPR was more present in obese patients
with all treatments, though prasugrel 10mg seemed to be more potent than
clopidogrel 150mg in obese patients. A study by Nawaz et al. showed that BMI
was inversely related to platelet inhibition by clopidogrel. Additionally they
saw, although in a small number of patients, that none of the underweight
patients (BMI <18.5) were found to be clopidogrel resistant.

The importance of adequate platelet inhibition by clopidogrel increases as
clopidogrel monotherapy can be a more prevalent treatment strategy in the
future, as more studies arise in which clopidogrel monotherapy is superior to
aspirin monotherapy in patients with CAD. The STOP-DAPT2 trial showed in mostly
stable CAD patients that clopidogrel monotherapy after 1 month of DAPT was
superior to 12 months of DAPT, reducing the risk of major and minor bleeding
without an increase in thrombotic events. The HOST-EXAM trial showed that
clopidogrel monotherapy is superior to aspirin monotherapy as chronic
maintenance therapy among patients who had successfully completed the required
duration of DAPT therapy post-PCI, both reducing the risk for thrombotic as for
bleeding events.

Clopidogrel 25mg
The dosage of clopidogrel 25mg is not yet routinely used in Europe. This lower
dosage has been produced to lower the bleeding risk in Asian patients and is
applied in the clinical practice in China. In a retrospective study aspirin
(100mg), clopidogrel (25mg) and clopidogrel (75mg) were compared in patients
after 12-month of DAPT after PCI. There was no significant difference in the
overall composite incidence of cardiac death, myocardial infarction and target
vessel revascularization in the three groups at three years after PCI. The
rates of bleeding (especially minor bleeding), gastrointestinal side-effects,
drug discontinuation and any blood transfusion were markedly lower in the
low-dose clopidogrel (25 mg) group than in the other two treatment groups
(P<0.05). Low-dose clopidogrel (50mg) plus aspirin was assumed safe in Japanese
patients directly after PCI, with only one stent-thrombosis (0.65%) in 126
patients after a follow-up of almost 14 months. In a small randomized pilot
study with 200 patients after PCI comparing clopidogrel 50mg vs clopidogrel
75mg, no myocardial infarction or stent-thrombosis occurred after more than 20
month of follow-up, suggesting that a low-dose clopidogrel treatment is safe in
the Japanese population.
In a study evaluating pharmacokinetics and bioequivalence of clopidogrel 25mg,
the absorption rate was lower and the absorption extent was higher than under
fasted condition, meaning that the pharmacokinetics

This study has been transitioned to CTIS with ID 2024-518890-33-00 check the CTIS register for the current data.

To determine if clopidogrel treatment can be optimized in patients with a low
or high BW/BMI compared to patients with a normal BW by adjusting the dosage of
clopidogrel and evaluating platelet reactivity measured using the VerifyNow.

This is a non-randomized single centre, prospective, experimental study in
patients with CCS treated with clopidogrel 75mg (and aspirin). This study is
designed to be pragmatic and is intended to be hypothesis generating. Patients
have to be treated with clopidogrel for at least one month without the
occurrence of a major bleeding event, an ischemic event (stroke, myocardial
infarction, or coronary revascularization) and have to be free of angina
complaints.

Eligible patients will be divided into three groups based on their BW or
BMI(according to ESC-consensus).
- Group 1 - Low BW: patients with a BW of <60kg or BMI <=18.5
- Group 2 - Normal BW: patients with a BW of 60-100kg and BMI of 18.5-30.
- Group 3 - High BW: patients with a BW of >=100 kg or BMI of >=30.

At baseline each patient is treated with clopidogrel 75mg and aspirin. At
baseline platelet reactivity will be measured and CYP2C19 genotype will be
analysed. For safety reasons patients in group 1 with high on-treatment
platelet reactivity when treated with clopidogrel 75mg, will be excluded for
further treatment adjustments, as it is possible that lowering the dosage of
clopidogrel will further worsen platelet reactivity and hence it would not be
ethical to lower the clopidogrel dose in these patients. Then the dosage of
clopidogrel treatment will be adapted for each group. After each alteration of
treatment a blood withdrawal takes place to measure platelet reactivity.

- Group 1: Clopidogrel 50mg QD for at least 10 days, then clopidogrel 25mg QD
for at least 10 days.
- Group 2: Clopidogrel 75mg
- Group 3: Clopidogrel 150mg QD for at least 10 days, then prasugrel 10mg QD
for at least 10 days.
In group 3 prasugrel is used as previous research has shown that a higher
clopidogrel dose of 150mg still is associated to high on-treatment platelet
reactivity, while with prasugrel high on-treatment platelet reactivity was less
common

There are no major risks or benefits for patients included in this study. A
maximum of three blood withdrawals obtained by venipuncture will be performed
in all study patients and patients will undergo pharyngeal swabs to analyse the
CYP2C19 genotype. All study patients have to be event-free for a month after
elective PCI and have to be treated with clopidogrel without any complications,
as the first month after PCI is the period that patients have the highest risk
for recurrent events.

Patients with a high BW/BMI are at higher risk for cardiovascular events and
have been associated with an inadequate response to clopidogrel treatment. We
hypothesize that these patients would benefit an dose adjustment to ensure
adequate platelet inhibition. In this study these patients possibly could
benefit the higher dose of clopidogrel as their risk for thrombotic events
could be lower. However, patients will be treated with the higher dose for a
short period of time, so the real benefit is estimated to be low. On the
contrary, a higher clopidogrel dose could lead to a higher bleeding risk. We
hypothesize that this bleeding risk is not higher than the bleeding risk in the
normal weight population treated with clopidogrel 75mg. On top of that, again
the period of time that patients are treated with the higher dose is short, so
the risk is estimated to be negligible.

Patients with a low BW/BMI will be treated with a lower dose of clopidogrel.
Treatment with a lower dose will lower their risk for bleeding. On the
contrary, this would potentially increase their thrombotic risk, however we
measure the degree of platelet reactivity before adjusting the dose and will
exclude patients who are already have HTPR. Hereby, we insure that only
patients with adequate platelet inhibition are treated with the lower dose.
Apart from the existing literature, showing that low dose clopidogrel can be
used safely in CAD patients in the Asian population, the period of time that
patients are treated with this lower dose is very short, further reducing the
potential risk for thrombotic events during the conduct of this study.