Primary Objective: Investigate the difference in composite endpoint MACE, major amputation, or target vessel revascularization in PAD Fontaine II patients with and without antiplatelet resistance as measured by a. VerifyNow b. Genetic testing of…
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Investigation of antiplatelet therapy resistance
a. Study parameters: antiplatelet resistance, genetic testing CYP2C19.
b. Primary endpoint:
ii. MACE, major amputation, target vessel revascularisation in PAD Fontaine II
patients.
Definitions of study parameters/endpoints
All definitions pertinent to PAD are based on the 2017 ESC Guidelines on the
Diagnosis and Treatment of Peripheral Arterial Disease, in collaboration with
the European Society for Vascular Surgery (ESVS).(8)
Adherence to drug treatment: Medication use includes therapy initiated 6 months
prior to the index date and up to 30 days after the index date. Treatment
adherence can be defined as the number of physiotherapy sessions prescribed for
walking therapy, and the estimated number of sessions completed. Drug adherence
can be estimated by calculating the number of pills prescribed and the
estimated number of pills taken each day.
Ankle-brachial Index of <0.90 is considered diagnostic for PAD, as well as a
significant decrease in ABI after exercise testing (see below).
Antiplatelet resistance is defined as that which is the result of high
antiplatelet reactivity or is associated with undesirable ischemic clinical
outcomes.(10) Table 2 in the protocol highlights the various definitions
provided in the literature(11):
Death will be defined as death from cardiovascular causes or cerebrovascular
causes and any death without another known cause. The information will be
obtained from patient files, referring vascular surgeons, general practitioners
or death certificates.
Exercise/treadmill test is usually performed using the Strandness protocol at a
speed of 3km/h and 10% slope. The test is stopped when the patient is unable to
walk further because of pain, defining maximal walking distance. Furthermore, a
post-exercise ankle SBP decrease of >30mmHg or a post-exercise ABI >20% is
diagnostic of PAD.
Exercise therapy is usually applied using the Strandness protocol at a speed of
3km/h and 10% slope. The test is stopped when the patient is unable to continue
walking due to limb pain. This is defined as the maximal walking distance. A
post-exercise ankle SBP decrease >30 mmHg or a post-exercise ABI decrease >20%
are diagnostic of PAD.(8)
Fontaine Classification: Clinical stages of lower extremity artery disease, see
Table 1(8)
MACE: Major adverse cardiovascular events include hospitalisation with the
diagnosis of nonfatal myocardial infarction, cardiovascular death or nonfatal
stroke.
Toe pressure <50mmHg is considered abnormal
Toe brachial Index <0.70 is considered abnormal
Secondary outcome
Investigate the prevalence of clopidogrel and aspirin resistance in the PAD
patient population
1. Progression of disease according to the Fontaine Classification.
Progression of disease is defined as:
i. Fontaine IIa/b and an intervention (endovascular/operation)
ii. Fontaine II to Fontaine III (with/without intervention)
iii. Fontaine II/III to Fontaine IV (with/without intervention)
2. Investigate the prevalence of CYP2C19 loss-of-function alleles in The Hague
region
3. Investigate the prevalence of antiplatelet therapy resistance with the
point-of-care VerifyNow Platelet Function Analyser.
4. Evaluate the percentage increase or decrease in all-cause mortality,
revascularisation, stent thrombosis in patients with and without antiplatelet
therapy resistance as measured by
i. VerifyNow
ii. Genetic testing of CYP2C19 loss-of-function alleles
Background summary
Epidemiology
Peripheral arterial disease (PAD) is a common vascular disease with a
preference for the lower extremities, and is estimated to affect 200 million
people worldwide, with the burden of disease presenting in the elderly
population.(1) PAD is caused by atherosclerosis, and progresses due to
increased arterial plaque formation and thus reduction in blood flow and oxygen
supply to the extremities. Reduced oxygen supply in the extremities leads to
symptoms such as ischemic pain, and the development and impaired healing of
ulcers. Risk factors for PAD include age, gender, ethnicity, smoking and
Diabetes Mellitus (DM).(2)
It is estimated that the population of persons 65 years old and over will
increase 44% in the coming 20 years. The prevalence of PAD in the general
population in the Netherlands is an estimated 7% to 56% in patients over 55 and
85 years old, respectively. For the larger The Hague area, this PAD prevalence
may be an underestimation as the population is of lower socio-economic status
(SES) and of larger multinational background including a large
Surinam-Hindustan community with a high-risk cardiovascular profile including
high rates of DM.
PAD can be divided into four stages according to the Fontaine classification
system, see Table 1.(3) Fontaine II includes patients with intermittent
claudication, and has a 5-year overall and vascular mortality rate of 9% and
3%, respectively.(4, 5) One-fifth of Fontaine II patients experience worsening
symptoms, and in some eventual amputation. Furthermore, Fontaine II is often
the index presenting symptom in patients with underlying cardiovascular
disease, with 21% of Fontaine II patients developing other cardiovascular
events in the course of five years.(5) While these numbers warrant extensive
secondary prevention and surveillance in PAD patients, current guidelines are
based on either recent small studies or dated larger American studies that may
no longer be relevant due to changing diagnostic and treatment strategies.(6)
There is thus a need for large contemporary studies on the epidemiology and
natural progression of Fontaine II patients.
Table 1: Fontaine Classification
FONTAINE CLASSIFICATION
STAGE Symptoms
I Asymptomatic
II IIa Non-disabling intermittent claudication
IIb Disabling intermittent claudication
III Ischaemic rest pain
IV Ulceration or gangrene
Treatment of Fontaine II PAD
Fontaine II PAD is generally considered a benign disease, but it has a large
impact on quality of life, as claudication symptoms can lead to limited
mobility with the potential for amputation in advancing cases. Prevention of
progression of disease and relief of intermittent claudication should initially
be attempted with supervised exercise therapy (SET).(7) By encouraging patients
to continue to walk, despite experiencing ischemic pain, collateral blood
vessel formation can be stimulated, improving the blood flow to the
peripheries. Furthermore, secondary prevention is initiated, including smoking
cessation advice and commencement of statins and platelet aggregation
inhibitors according to local guidelines.
Secondary prevention with platelet aggregation inhibitors
European PAD guidelines advocate for the treatment of PAD with clopidogrel,
with aspirin as the second-choice antiplatelet agent.(8) However, despite
adhering to antiplatelet therapy, a significant proportion of the PAD patient
population will suffer an ischemic cardiovascular event. Increasing evidence
shows aspirin resistance or clopidogrel resistance to be associated with a
higher risk of ischemic events in adherent patients.(9) Current research
focuses on the presence of antiplatelet resistance in patients with advanced
cardiovascular disease with significant results, but with limited studies
exploring this phenomenon in PAD patients.(10) Historically, light transmission
aggregometry was used to measure platelet aggregation, but this procedure is
time intensive and requires laboratory technical skills.(11) Antiplatelet
resistance testing has advanced into point-of-care analysers, such as the
VerifyNow system. The VerifyNow assay can be used to measure clopidogrel or
aspirin resistance, depending on the use of a P2Y12- or Arachadonic Acid Assay,
respectively.(12, 13) No consensus has been reached as to the optimal cut-off
value for antiplatelet resistance, largely due to the small retrospective
nature of the studies conducted in this field.(10)
Clopidogrel resistance can be due to a genetic polymorphism, as well as
patient-related factors such as DM or renal failure. A polymorphism in the
CYP2C19 gene can result in reduced metabolism of clopidogrel, diminishing its*
antiplatelet inhibitor function.(14) The most common CYP2C19 loss-of-function
alleles are 1-3. Allele 2 loss-of-function most frequently occurs, in ~15% of
Caucasians and Africans and 29-35% of Asians.(15) Patients can be classified
according to the CYP2C19 polymorphism expression. Individuals homozygous for
two loss-of-function alleles are said to be poor metabolisers (PM); those
heterozygous for one loss-of-function allele are intermediate metabolisers
(IM); and subjects with a wild type genetic profile are extensive metabolisers
(EM). (16, 17) Previous research has shown that being a poor metaboliser has a
negative effect on clinical outcomes.(14, 16) The prevalence of
loss-of-function alleles therefore differs per ethnic group and as such it is
unclear what the prevalence is in the multi-ethnic population of the Hague, and
whether it would be appropriate to adapt the antiplatelet treatment strategy
based on regional epidemiological data.
Hypothesis and Rationale
It is hypothesized that resistance to antiplatelet therapy is a risk factor for
progression of disease, MACE and secondary outcomes such as increased need for
revascularisation, or a higher incidence of in-stent thrombosis.
Study objective
Primary Objective:
Investigate the difference in composite endpoint MACE, major amputation, or
target vessel revascularization in PAD Fontaine II patients with and without
antiplatelet resistance as measured by
a. VerifyNow
b. Genetic testing of CYP2C19 loss-of-function alleles
Study design
This study will be performed in The Hague, the Netherlands and include patients
receiving care in the Haaglanden Medical Centre and the General Practitioners
in this region.
Prospective cohort study
To prospectively determine the prevalence and effect of antiplatelet therapy
resistance on disease progression and adverse events.
Point-of-care antiplatelet resistance blood tests and CYP2C19 genotyping will
be performed in patients in a hospital setting.
1. VerifyNow: clopidogrel and aspirin resistance blood tests
2. Genotyping: gold standard - laboratory genetic tests
Patients will be divided into cases (antiplatelet resistant) and controls (not
antiplatelet resistant) based on VerifyNow results. According to genetic
testing patients will be divided into extensive-, intermediate- and poor
metabolisers. Blood sample for genetic testing will be collected at inclusion
and collectively analysed upon completion of the study.
Study burden and risks
An added risk for participants of this study is due to venipuncture. This
procedure is low risk, and subject may develop a hematoma post-procedure.
Participation in this study will require venipuncture for the VerifyNow and
CYP2C19 genetic test during the primary consultation. Furthermore, at a regular
follow-up visit at 4 months a second VerifyNow measurement will be performed.
The patient will be required to fill out a questionnaire four times during the
study period.
Lijnbaan 32
Den Haag 2512VA
NL
Lijnbaan 32
Den Haag 2512VA
NL
Listed location countries
Age
Inclusion criteria
18 years of age and older
Suggestion of peripheral arterial disease Fontaine II: claudication pain in the
limb; ABI <0.9, DUS >50% stenosis.
Antiplatelet therapy: clopidogrel
Exclusion criteria
Unable to give informed consent or have a life expectancy of less than one year
due to a non-cardiovascular risk profile
Design
Recruitment
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| CCMO | NL81458.058.22 |