University of Groningen
Chronic limb-threatening ischemia
Ipema, Jetty
DOI:
10.33612/diss.170945328
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Publication date:
2021
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Citation for published version (APA):
Ipema, J. (2021). Chronic limb-threatening ischemia: Optimizing endovascular and medical treatment.
University of Groningen. https://doi.org/10.33612/diss.170945328
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1
During the 2 years of research for this PhD, an estimated 21.6 million
people were diagnosed with peripheral arterial disease (PAD) worldwide,
according to numbers from the Global Burden of Disease.
1In 2017, the
worldwide prevalence of PAD patients was 118.1 million, accounting for
70.200 deaths.
1The prevalence of PAD increases with age, and with the
current aging population, it will be even higher in the next decade. An
increase in prevalence of 23.5% was already observed between 2000 and 2010.
2Because of the lack of screening programs for PAD, it is expected that many
people are undiagnosed and untreated and that the real number is even higher.
PAD is clearly a global health problem. In the early stages, PAD patients
experience claudication, which may progress to chronic limb-threatening
ischemia (CLTI) comprising ischemic rest pain and impaired wound healing. All
stages of PAD are accompanied by high mortality and morbidity rates, mostly
caused by cardiovascular and especially coronary artery disease. The 5-year
mortality rate is approximately 30% for patients with claudication and 60%
for patients with CLTI, which is higher than for most cancers.
3,4Furthermore,
50% of the patients with PAD have limited mobility and poor quality of life.
5The main cause of PAD is atherosclerosis. Treatment starts with
reducing the risk factors, secondary prevention, and supervised exercise
therapy. Risk factors, besides age, are smoking, hypertension, hyperlipidemia,
diabetes mellitus, obesity, other cardiovascular diseases, male sex, and familial
predisposition.
6–8Change of dietary habits and physical activity are important
components of secondary prevention to reduce obesity. Antiplatelets, statins,
angiotensin-converting enzyme inhibitors, and smoking cessation have
been shown to significantly reduce rates of major adverse cardiac events
(hazard ratio [HR]: 0.64; 95% confidence interval [CI]: 0.45 to 0.89; p = 0.009),
major adverse limb events (HR: 0.55; 95% CI: 0.37 to 0.83; p = 0.005), and
mortality (HR: 0.56; 95% CI: 0.38 to 0.82; p = 0.003) compared with patients
who do not adhere to all of these preventive measures.
9Furthermore,
supervised exercise therapy as a primary treatment has been shown to
significantly reduce the risk of secondary revascularization and death
compared with patients who undergo revascularization primarily.
10However, many patients with disease progression need surgical or
endovascular revascularization. Nowadays, endovascular treatment is often
preferred over surgery, because it is less invasive and there is no need for
general anesthesia in this often high-risk group of patients.
11–13Endovascular treatment
In recent years, endovascular techniques have been highly developed. It started
with what is now called plain-old balloon angioplasty (POBA), with or without
additional bare-metal stenting (BMS). Although good results were observed
in the treatment of the iliac arteries, restenosis rates were higher in the more
distal segments.
12Drug-coated balloons (DCBs) were introduced to overcome
this problem, because the drugs have antiproliferative properties that could
reduce neointimal hyperplasia of the vessel wall.
12Paclitaxel is one of the drugs
used in DCBs. During balloon inflation, paclitaxel particles are transmitted
into the vessel wall where they dissolve slowly over 2 months and inhibit the
proliferation of endothelial cells.
14DCBs with paclitaxel have shown good results
in the treatment of the femoropopliteal artery.
15,16Despite this, paclitaxel-
coated balloons are currently a topic of discussion, because some studies showed
higher mortality rates with this type of DCB compared with POBA.
17,18Another type of DCB with antiproliferative properties is the
sirolimus-coated balloon. Sirolimus is less toxic than paclitaxel, but due to its hydrophilic
nature, sustained drug release and retention in the vessel wall are difficult,
limiting the use of sirolimus.
19Besides DCBs, drug-eluting stents (DESs) were developed to overcome
post-intervention restenosis. Some of these DESs contain paclitaxel, and others
elute everolimus. Everolimus inhibits the proliferation of smooth muscle cells
and thereby neointimal hyperplasia. As a result of its lipophilic properties, it is
rapidly absorbed into the injured vessel wall.
20The advantage of DESs over
DCBs is that drug elution takes place over a longer period of time.
21DESs, on
the other hand, are permanent implants that cause damage to the vessel wall,
in contrast with DCBs, of which nothing is left behind. Although DCBs and DESs
have both been shown to be superior over POBA and BMSs for femoropopliteal
revascularization,
22–24the costs are higher compared with POBA and BMS.
25,26In addition, restenosis rates still remain, and scaffold-induced thrombosis
occurs.
To minimize disadvantages of the presence of permanent metallic stents,
the latest development is the bioresorbable scaffold. This type of stent, also
containing an antiproliferative drug, completely dissolves within a few
months to years.
27,28Contrary to permanent scaffolds, it does not hinder future
interventions or initiate late lumen loss.
29–31However, the first-generation
bioresorbable scaffolds used in cardiac disease were associated with high rates
of adverse events and were even drawn back from the market.
32Therefore, the
use of these bioresorbable scaffolds in peripheral arteries has to be further
explored.
Medical treatment
Besides revascularization, medical therapy has a place in the management
of PAD patients and serves two goals. The first is prevention from
cardiovascular events such as myocardial infarction, cerebrovascular
accidents, or vascular death. Antiplatelets have shown to reduce major
adverse cardiac events with 18.2%.
33Other medications that serve as
secondary prevention in PAD patients are lipid-lowering, antihypertensive,
and glucose-lowering medications.
13,34,35Smoking cessation, dietary habits, and
lifestyle changes are also essential.
36Secondary prevention has been shown
to significantly reduce major adverse cardiac events, major adverse limb
events, and mortality, but most patients with PAD do not receive the complete
guideline-recommended medical treatment.
9,37Despite secondary prevention,
the 1-year rate of death, myocardial infarction, stroke, or hospitalization for
atherothrombotic events was found to be 17% among PAD patients.
38Because
severity of the disease is associated with a worse prognosis, the rates for
patients with CLTI are even higher, with an annual mortality rate of 25%.
6,39The second goal is prevention from atherosclerotic limb events to
improve limb salvage and wound healing. Antiplatelet medications are
commonly prescribed after revascularization. Different types of antiplatelets
are used, of which aspirin and clopidogrel are the most common, and the
combination of these two is also prescribed. However, high on-treatment
platelet reactivity is a phenomenon that is becoming more and more an
issue.
40,41Therefore, other types of antiplatelets and anticoagulation are
being studied.
42–44Newer therapies, such as stem cell and gene therapy, are
upcoming to try to improve limb salvage and wound healing in patients with
CLTI.
Aims and outlines of this thesis
This thesis is divided in two parts. The first part focuses on clinical outcomes
and patency rates after different endovascular therapies for PAD and mainly
CLTI patients. The second part investigates the added value of medical
therapy, with emphasis on antiplatelet regimens in PAD and CLTI patients.
A 2016 meta-analysis of the use of DCBs in the femoropopliteal segment
caused commotion in the vascular world because it showed a higher
mortality rate for patients treated with paclitaxel-impregnated DCBs
compared with patients treated with POBA. Hence, a systematic review
and meta-analysis was performed to investigate the 1-year mortality rate
and limb outcomes in below-the-knee (BTK) arteries (Chapter 2).
In addition to balloon angioplasty, different types of DESs have been
introduced. One of these is the Eluvia stent (Boston Scientific,
Marlborough, MA, USA), which releases paclitaxel and was built on the same
stent platform as the earlier Innova stent (Boston Scientific, Marlborough,
MA, USA), which was designed especially for the femoropopliteal arteries.
The stent has been studied in claudicant patients with short lesions, but
little evidence is available on the use of the Eluvia stent for long,
severely calcified lesions, which is the focus of the study described in
Chapter 3.
Bioresorbable scaffolds have recently been introduced for endovascular
repair; however, little is yet known about the clinical and radiologic outcomes
of their use in BTK arteries. 1-year single-center outcomes in 41 Asian patients
with severe disease and comorbidities are retrospectively studied in Chapter
results of available studies of bioresorbable scaffold use in BTK arteries.
Lastly, 2-year outcomes of 121 patients treated with 189 bioresorbable
scaffolds from three different centers are retrospectively investigated in
Chapter 6.
Even though endovascular revascularization techniques are highly
developed, measuring changes in tissue perfusion during revascularization
procedures is difficult. Two-dimensional perfusion angiography (2DPA)
is a software tool that may do so, but the tool had not been validated
in CLTI patients. Therefore, Chapter 7 studies the reproducibility and
intra- and interobserver variability of 2DPA in this patient population. The
results can be used to further explore the value of 2DPA in CLTI patients.
Part 2 of this thesis involves the medical treatment of PAD patients. First,
an overview of available medical regimens for CLTI patients is shown
(Chapter 8). The rest of this thesis is focused on one of the cornerstones
of medical treatment in PAD patients: antiplatelet therapy (APT).
Although APT has been widely used, there is still no consensus among
the international guidelines regarding the type of APT patients
should receive after different revascularization strategies.
11–13,45,46The current APT prescription patterns among 139 vascular surgeons in the
Netherlands and a literature overview on APT are studied in Chapter 9.
A specific point of discussion on APT is the prescription of single
versus dual APT after endovascular treatment. There is no consensus
in the literature and no uniform protocol among therapists.
11–13,45–50Therefore,
Chapter 10 tries to find an answer to the question whether dual APT
is preferred over single APT, especially for femoropopliteal stented
lesions and BTK revascularizations. A retrospective study among 237
patients was performed in three centers.
The thesis ends with Chapter 11, which provides a summary, general
discussion, and future perspectives.
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