Introduction
The link between inflammation and acute coronary
syndrome (ACS) remains to be sufficiently elucidated. It has been
previously suggested that there is an inflammatory process
associated with ACS. Activation of the local inflammatory process
leads to damage of the endothelium. This mechanism leads to the
dysfunction of the endothelium, altering its antithrombotic
properties (1).
In the past, plaque rupture was considered the only
pathophysiological process behind ACS (2). In the past few years, numerous
mechanisms have been found to be involved in the pathogenesis of
ACS. In an excellent review, Crea and Libby (3) suggested plaque erosion in addition to
plaque rupture as a mechanism for ACS. This process can be with or
without inflammation. The presence of inflammation associated with
plaque rupture or erosion may have clinical implications.
Considering this, it is mandatory that inflammation become a target
for therapy Increased concentrations of highly sensitive C-reactive
protein (hs-CRP) and the release of cytokines including tumor
necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-8 in unstable
angina and myocardial infarction (MI) (4,5), have
been identified in patients with ACS. In addition, high levels of
IL-6 have been described in patients with unstable angina and these
patients had a worse outcome (6).
Previous findings have shown that high levels of
hs-CRP are an independent risk factor for coronary syndromes. High
levels of hs-CRP highlight the inflammatory process associated with
the progression of atherosclerosis albeit not necessarily with ACS
(7). Patients with levels of hs-CRP
>2 mg/l were associated with more major adverse cardiovascular
events (MACEs), as reported by a cohort study in Switzerland
(8). High levels of hs-CRP have
been reported up to three months in >50% of patients with ACS
despite optimal medical treatment (9). The revascularization procedures
[percutaneous coronary intervention (PCI) or coronary artery
by-pass grafting (CABG)] that patients with ACS undergo may cause
myocardial injury and can add to the inflammation process (10).
Pentoxifylline was used in the treatment of patients
with intermittent claudication due to its blood rheology properties
(11). Some clinical trials
utilizing pentoxifylline suggest that this drug may potentially
delay the progression of atherosclerosis and reduce the risk of
vascular events, especially by modulating the systemic inflammatory
response (12). The molecular
biology underlying these various effects is not well known. In a
previously published meta-analysis, the results showed that
pentoxifylline did not change the levels of blood pressure (BP) or
plasma IL-6 concentration, although it decreased circulating TNF-α
and hs-CRP concentrations (13).
Adding pentoxifylline to dual antiplatelet
therapy-DAPT (aspirin + clopidogrel) is not associated with
increased platelet inhibitory effects in patients with coronary
artery disease receiving DAPT, thus no increase in bleeding
complications were identified (14).
Pentoxifylline was used in the treatment of patients
with intermittent claudication due to its blood rheology properties
(11). Some clinical trials
utilizing pentoxifylline suggest that this drug may potentially
delay the progression of atherosclerosis and reduce the risk of
vascular events, especially by modulating the systemic inflammatory
response (12). The molecular
biology underlying these various effects is not well known. In a
previously published meta-analysis, the results showed that
pentoxifylline did not change the levels of BP or plasma IL-6
concentration, although it decreased circulating TNF-α and hs-CRP
concentrations (13).
Adding pentoxifylline to dual antiplatelet
therapy-DAPT (aspirin + clopidogrel) is not associated with
increased platelet inhibitory effects in patients with coronary
artery disease receiving DAPT, thus no increase in bleeding
complications were identified (14).
Patients and methods
Ethics approval and informed
consent
The patients were recruited from the Cardiovascular
Disease Institute, Timisoara, Romania. Prior to commencement of the
study, all patients included in our study granted written informed
consent. Approval for the study (no. 8461/04.12.2018) was obtained
from the Ethics Committee of the Cardiovascular Disease Institute
(Timisoara, Romania).
Inclusion and exclusion criteria
Inclusion criteria were represented by prolonged
chest pain 24 h or within the past week prior to enrollment, ECG
changes (ST depression or negative T waves) with positive
high-sensitive troponin levels. Exclusion criteria were the
presence of malignancy, pregnancy, stroke within the previous 3
months, renal or hepatic diseases, severe heart failure with left
ventricular ejection fraction of <35%, as well as
contraindications to pentoxifylline treatment and chronic
anticoagulation therapy. ST elevation myocardial infarction (STEMI)
patients were also excluded from randomization because they were
subjects in another study.
Patient data
Patients were included in the present study over the
period December 2018 to May 2020; the last trial control was in
June 2021. A total of 500 patients were included in the present
study and randomized equally into groups A and B. The mean age was
62.3±10.3 years. Of the 500 patients, 80.4% were male, 20.8% had
diabetes, 49.4% had hypertension, and 42% were currently
smoking.
Patients were randomized to receive standard
therapy, i.e., aspirin, clopidogrel or ticagrelor, and statin plus
placebo in one arm (group A). In the other arm (group B),
pentoxifylline 400 mg TID was added to the standard therapy.
Coronary angiography was performed in all the patients enrolled in
the study, 0-72 h after admission, according to the European
Society of Cardiology (ESC) guidelines recommendations (15). All the patients who needed
revascularization (interventional or surgical) were treated
according to ESC recommendations (16). The patients were followed up at 1, 3
and 6 months after inclusion in the study. Levels of IL-6, TNF α,
hs CRP were assessed at baseline (T0), 48 h (T1) and 15 days
(T2).
Study end points
As a primary outcome, the MACEs [defined as a
composite of ACS (recurrent angina, MI), ischemic-driven
revascularization, death from any cause or stroke] at 1 year were
assessed. An additional secondary composite endpoint was to
determine the way pentoxifylline treatment affected stent
restenosis in patients with PCI revascularization on admission and
the levels of hs-CRP and IL-6, and TNF-α.
Statistical analysis
The statistical analysis was performed using
CsS/Statistics 3.1 software (StatSoft Corp.) and EPI INFO 6.04. The
Student's t-test and log rank test were used to make comparisons
and determine differences between the two groups. Relative risk
(RR) and 95% confidence interval (95% CI) were also obtained. In
the primary outcome, a linear regression model, and a Wald test
were used to reject the null hypothesis. Data are reported as RRs
with 95% CI. P<0.05 was considered to indicate statistical
significance.
Results
Patient data
A total of 500 patients were screened and divided
into two groups (with 250 being assigned to group A and 250 to
group B). Patients were followed up for a median of 20 months after
being included in the study. The mean age of the participants was
62.3±10.3 years, 80.4% were male, 20.8% had diabetes, 49.4% had
hypertension, and 42% were current smokers. In addition, following
admission, 59.4% had hs-CRP ≥2 mg/l and all 500 patients had
abnormal troponin at baseline. The revascularization procedures
were introduced: 87.4% patients underwent PCI and the remaining
patients were treated with medication or underwent CABG according
to the ESC guidelines.
Patient characteristics at
baseline
The trial medication was discontinued in 16.4% of
patients in group A (n=41) and in 16% of patients in group B
(n=40). They were considered dropouts and were excluded from the
final analysis. In group A, 209 patients remained and in group B,
210 patients remained. Patient characteristics at baseline are
presented in Table I. There was no
major side effect reported in the two groups. Patients in group B
(n=5, 1%) complained of abdominal discomfort and nausea, headache
(n=3, 0.6%) but did not discontinue the medication. Symptoms
disappeared before discharge.
 | Table IBaseline characteristics. |
Table I
Baseline characteristics.
| Characteristics | Group A: Standard
therapy and placebo (n=209) | Group B:
Pentoxifylline added to standard therapy (n=210) |
|---|
| Age (years) | 61.8±10.2 | 62.3±10.7 |
| Male sex [no.
(%)] | 167 (79.9%) | 168 (80%) |
| Body mass index,
kg/m2 | 29±4.8 | 28.8±5.2 |
| Current smoking [no.
(%)] | 83 (39.7%) | 84 (40%) |
| Diabetes [no.
(%)] | 40 (19.13%) | 42 (20%) |
| Hypertension [no.
(%)] | 105 (50.2%) | 102 (48.5%) |
| History of PCI [no.
(%)] | 30 (14.42%) | 32 (15.23%) |
| History of CABG [no.
(%)] | 10 (4.78%) | 10 (4.76%) |
| hs-CRP ≥2 mg/l [no.
(%)] | 126 (60.28%) | 128 (60.95%) |
| Patients who
underwent PCI [no. (%)] | 184 (88%) | 183 (87.14%) |
Another important aspect in the present study was
the evolution of inflammatory markers. CRP, TNF-α and IL-6 levels
at baseline were examined at 24 h and at 1 month. The secondary
outcome for this study was the effect of adding pentoxifylline [400
mg TID to standard therapy on inflammatory markers (hs-CRP, TNF-α,
and IL-6 level)] and the correlation between that level of
inflammatory marker and the rate of MACEs at 1 year.
At admission, the median IL-6 level was 7.3±5.1 pg/l
in group A vs. 7.2±4.8 pg/l in group B [P=NS (not significant)],
median hs-CRP level was 1.35±1.2 mg/l in group A vs. 1.25±1.2 mg/l
in group B (P=NS) and the median TNF-α level was 34.5±14.8 pg/l in
group A vs. 33.4±14.2 pg/l in group B (P=NS). It was found that at
48 h (T1) there was an attenuation of rise in the hs-CRP and TNF-α
levels in group B after administration of pentoxifylline compared
with group A that received a placebo. Administration of
pentoxifylline in group B attenuated the increase in hs-CRP from
baseline (1.25±1.2 mg/l) to 48 h (5.3±1.6 mg/l) when compared with
group A (baseline, 1.35±1.2 mg/l and 48 h, 8.9±2.2 mg/l,
P<0.001). Regarding the TNF-α level, administration of
pentoxifylline reduced the level in group B at 48 h (at admission
33.4±14.2 pg/l and 23±19.3 pg/l at 48 h), but not in group A (at
admission 34.5±14.8 pg/l, P=NS and 43.3±18.5 pg/l at T1,
P<0.001). This finding did not apply to the IL-6 level which was
not affected by administration of pentoxifylline (group A at T0,
7.3±5.1 pg/l and at T1, 24.4±8.6 pg/l; group B at T0, 7.2±4.8 pg/l
and at T1, 24.4±8.6 pg/l, P=NS). In addition, at 15 days (T2), it
was noted that administration of pentoxifylline in group B
normalized earlier the hs-CRP and TNF-α level compared with group A
(hs-CRP: group A at T2, 4.4±2.5 mg/l vs. group B at T2, 1.2±1.0
mg/l, P<0.001; TNF-α: group A at T2, 10.2±7.3 pg/l vs. group B
at T2, 6.2±3.4 pg/l, P<0.001). This did not apply to the IL-6
level at T2 (IL-6: group A at T2, 12.5±6.5 pg/l vs. group B at T2,
11.3±7.2 pg/l, P=NS).
Primary endpoint
MACEs were present in 12.38% (n=26) in group B, and
in 15.78% (n=33) in group A (RR, 0.78; 95% CI, 0.486-0.1.263;
P=0.40). RR for the components of the primary endpoint, including
death (RR, 0.93; 95% CI, 0.48-1.80, P=0.84), non-fatal MI (RR, 1.1;
95% CI, 0.39-3.39, P=0.78), stroke (RR, 0.99; 95% CI, 0.14-6.99,
P=0.99), and the need for coronary revascularization (RR, 0.12; 95%
CI, 0.015-0.985, P=0.048) are presented in Table II.
| Table IIPrimary clinical endpoints. |
Table II
Primary clinical endpoints.
| Components of primary
end points | Group A (n=209) | Group B (n=210) | Relative Risk (RR)
(95% CI) | P-value |
|---|
| Death | 17 (8.13%) | 16 (7.61%) | 0.93 (0.48-1.80) | P=0.84 |
| Non-fatal MI | 6 (2.87%) | 7 (3.33%) | 1.1 (0.39-3.39) | P=0.78 |
| Stroke | 2 (0.95%) | 2 (0.95%) | 0.99 (0.14-6.99) | P=0.99 |
| Coronary
revascularization | 8 (3.82%) | 1 (0.47%) | 0.12
(0.015-0.985) | P=0.048 |
Discussion
Adding pentoxifylline 400 mg three times a day (TID)
to standard therapy in ACS patients may improve clinical outcome,
reducing proinflammatory and increasing the anti-inflammatory
response. Treating inflammation in ACS is a fact to be considered
when selecting medication. (11,17).
CABG is associated with a high inflammatory state.
Administration of pentoxifylline before surgery was found to
decrease the intensive care unit stay, ventilation time by reducing
TNF-α and IL-6 levels, without influenced the troponin level
(11,18,19).
In the present study, administration of
pentoxifylline in patients with high inflammatory state (ACS)
reduced the level of hs-CRP, TNF-α but not IL-6.
In a study by Altman et al (20), meloxicam, an anti-inflammatory drug,
was added to heparin and aspirin in the treatment of patients with
ACS without ST elevation. The study supports our hypothesis of the
potential benefits of anti-inflammatory treatment (meloxicam in
this case), and that inhibition of inflammation may decrease
short-term events, mainly the occurrence of angina pectoris and
revascularization in ACS patients without ST-segment elevation.
The outcome of patients with ACS might be improved
by administration of anti-inflammatory drugs that lower the levels
of IL-1 and IL-6 as previously shown (21-23).
In the MRC-ILA Heart study administration, anakinra (an IL-1
receptor antagonist) reduced the level of hs-CRP without affecting
troponin but with a high rate of MACEs at 3-month follow-up
(24).
Kleveland et al (25) used tocilizumab to block the IL-6
receptors as an anti-inflammatory drug in patients with non-ST
elevation myocardial infarction (NSTEMI). They concluded that
tocilizumab attenuated the inflammatory response (reduced hs-CRP
levels) and the level of myocardial injury after PCI (troponin
level was low in the tocilizumab group) but did not reduce
cardiovascular outcomes.
In another study, the use of colchicine treatment
for five days in STEMI patients did not improve the outcome of the
patients (26). In the COMPlement
inhibition in MI treated with thrombolytics (COMPLY) study, the
role of a novel C5 complement monoclonal antibody fragment
pexelizumab was investigated. The administration of pexelizumab did
not reduce infarct size or improve clinical outcome (27). Identical results as those obtained
in the COMPlement inhibition were obtained in the MI treated with
angioplasty (COMMA) trial (28,29).
A meta-analysis aiming to assess the risk/benefit
profile of pexelizumab (bolus + infusion) vs. a placebo in addition
to current medication in the management of patients with STEMI or
undergoing coronary artery bypass showed no benefit, but concluded
that it may reduce the risk of death in patients revascularized by
coronary artery bypass grafting (30).
Administration of varespladib (a non-specific pan
sPLA2 inhibitor) had favorable effects on atherosclerotic plaques,
as shown in the Vista-16 study (31). The Colchicine Cardiovascular
Outcomes Trial (COLCOT) used colchicine as an anti-inflammatory
drug in patients with ACS. They found a lower incidence of MACE in
the colchicine arm due to a reduced need for coronary
revascularization and lower stroke number (32,33).
There are few studies of pentoxifylline in ACS. In a
group of STEMI patients, the authors administered 1,200 mg
pentoxifylline before thrombolytic but no benefit regarding MACEs
and biomarker levels was observed (34). Previous findings have shown that
pentoxifylline may exert an anti-inflammatory effect and
administration in ACS could be beneficial (17).
To the best of our knowledge, the present study is
the first that uses pentoxifylline in patients with ACS (NSTEMI)
with primary endpoint represented by MACEs and secondary endpoints
being the level of inflammatory markers.
The results showed that there were no differences
between groups regarding MACEs as the primary endpoint but adding
pentoxifylline was associated with a lower need of coronary
revascularization (RR, 0.12; 95% CI, 0.015-0.99, P=0.004). This
result was probably determined by the low number of acute stent
thrombosis events and restenosis in the pentoxifylline group.
Adding pentoxifylline to standard therapy in ACS patients could
influence the inflammatory marker level. In the present study, the
addition of pentoxifylline to standard treatment in patients with
ACS reduced the increase in hs-CRP and TNF-α levels and caused
early normalization but did not influence the IL-6 level.
There are several limitations to the present study.
This was a single-center experience study, not a multicenter trial.
Secondly, it was not a double-blinded randomized trial. Thirdly,
the number of patients included was small and this may have
affected the overall results of the trial. Therefore, the power of
an adequate sample size to demonstrate the benefit of
pentoxifylline in ACS is lacking.
In conclusion, the addition of pentoxifylline to
standard treatment in patients with ACS reduced the rise of hs-CRP
and TNF levels and caused early normalization but did not influence
the IL-6 level. This attenuation in inflammation did not improve
MACEs at 1 year, although it may have some benefit on coronary
revascularization. These results suggest a potential benefit of
adding pentoxifylline to standard treatment in patients with
non-STEMI ACS, but further clinical trials are needed in order to
draw definitive conclusions.
Acknowledgements
Professional editing, linguistic and technical
assistance performed by Irina Radu, Individual Service Provider
(credentials: E0048/2014, Medicine-Pharmacy).
Funding
Funding: No funding was received.
Availability of data and materials
Corresponding author will provide all supplementary
data and materials by request. The materials are not publicly
available to limit the amount of publicly available personal
information, as classified by the European Union General Data
Protection Regulation.
Authors' contributions
DMB and LP contributed to the study conception and
design. DMB, DAB, MB, CTL and CM were involved in the investigation
of patients, collection of resources, and analysis and
interpretation of results. DMB and LP drafted and wrote the
manuscript. All the authors have read and approved the final
article. DMB and LP confirmed the authenticity of the raw data.
Ethics approval and consent to
participate
Approval of the study (8461/04.12.2018) was provided
by the Ethics committee of the Cardiovascular Disease Institute
Timisoara (Romania). Written informed consent was obtained from
patients prior to enrollment.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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