atpci journal club

1. Efficacy and safety of trimetazidine after
percutaneous coronary intervention (ATPCI)
JOURNAL CLUB

2. TRIMETAZIDINE
 A 2nd line anti-ischemic agent
 Unlike conventional drugs, it exerts no effect on
coronary flow, contractility, blood pressure, or heart
rate
 European Cardiology Society advocates this
medication as a second-line therapy in patients
with angina.
 Not approved by FDA in USA

5.  During mild to moderate cardiac ischaemia, myocardial cells respond by accelerating glucose uptake to generate enough ATP to
maintain ionic gradients and calcium homeostasis.
 Paradoxically, during prolonged and severe ischaemia, the myocardium continues to derive most of its energy from beta-oxidation
despite a high rate of lactate production. In this condition, high rates of fatty acid oxidation further inhibit glucose oxidation due to
competitive interaction, known as the Randle mechanism

6.  Therefore, when there is a low availability of oxygen,
fatty acid oxidation has an unfavourable effect on cells
 requiring more oxygen
 producing less ATP
 more reactive oxygen species (ROS)
 further depressing mitochondrial respiratory efficiency
 These metabolic changes are responsible for metabolic,
morphological and functional alteration of the
myocardium leading to arrhythmias and contractive
failure.

7. Mechanism as anti anginal
Inhibits the long-chain 3-ketoacyl coenzyme A thiolase (LC 3-KAT), final
enzyme in the FFA b-oxidation pathway
Increases pyruvate dehydrogenase activity
Increased the metabolic rate of glucose
Decreased oxygen consumption during adenosine triphosphate (ATP) synthesis,
hydrogen ion production, reduced calcium ion accumulation
Reduced accumulation of sodium in cardiomyocyte cytoplasm
Decreased formation of reactive oxygen species (ROS)
Reduced neutrophil infiltration

9. Other actions
Other actions
Chronic heart failure (CHF)
inhibition of cardiac fibrosis
reduced collagen accumulation, by decresing
connective tissue growth factor (CTGF) expression
in cardiac fibroblasts
Decreasing nicotinamide adenine dinucleotide
phosphate-oxidase (NADPH oxidase) levels, and
ROS production
Inhibition of reperfusion injury Increase microRNA-21
up-regulates the activity of Akt signalling
resulting in a decrease in the ratio of bax/bcl-2 and
also the expression of caspase-3
ultimate effect being a reduction in
hypoxia/reperfusion-induced apoptosis
enhancement of the mechanical resistance of the
sarcolemma.
Proposed benefits-
Improved microvascular dysfunction
Decreased incidence of CIN
Symptomatic improvement in PVD pts
Improve symptoms of chronic heart failure but also effect an improvement in cardiac
ejection fraction (EF)

10.  1) and determines the increase in glucose oxidation, energetically useful in HF.
 (2) Limitation of accumulation of sodium and calcium and intracellular acidosis.
 (3) Reduces reactive oxygen species (ROS)-induced cell damage, and inhibits cardiac fibrosis and
inflammation through the ROS/CTGF pathway.
 (4) Prevention of cell apoptosis through the mitogen-activated protein kinase (MAPK)/AKT
pathway.
 (5) Reduces uncoupling proteins (UCP) and increases PCr/ATP ratio

11. Adverse effects
 Gastrointestinal disturbances, vomiting, nausea
 thrombocytopenia, agranulocytosis and liver dysfunction
 episodes of headache
 Main identified trimetazidine-induced serious ADR is connected to
Parkinson syndrome and related symptoms (tremor)
 extrapyramidal symptoms have a very low prevalence (incidence
of 0.36/100,000 person-years) and are generally reversible after
trimetazidine withdrawal
 Patients receiving the treatment over a very long time, mainly in
cardiology indications, aged more than 75 years old are from the
group at the highest risk of this complication occurrence.
 Patients with severe renal impairment (creatinine clearance 30
ml/min), trimetazidine should not be used

12. TRIMetazidine in POLand (TRIMPOL)-II
study-2001
 Randomized, multicentre, double-blind, placebo-controlled
parallel group study
 Total of 426 male and female patients with stable, effort
induced angina and documented coronary artery disease
 Received either placebo or trimetazidine 20mg three times
daily in addition to metoprolol 50mg twice daily.
 Treadmill exercise tests were performed at weeks (−1), 0, 4
and 12.

13. significant improvement in the trimetazidine group (as compared with
placebo) for the following parameters:
total exercise duration (+20.1 s, p = 0.023)
total workload (+0.54 metabolic equivalents [METs], p = 0.001)
time to 1-mm ST-segment depression (+33.4 s, p = 0.003)
time to onset of angina (+33.9 s, p<0.001)
angina attacks/week (-0.73, p = 0.014)
the necessity of short-acting nitrates administration per week (- 0.63, p =
0.032)

14. Efficacy of trimetazidine on functional capacity in
symptomatic patients with stable exertional angina--the
VASCO-angina study-2012
 A randomised double-blinded, placebo-controlled trial
 Assessed anti-anginal efficacy and safety of standard and high dose of modified-
release TMZ (70 mg/d and 140 mg/d) in symptomatic and asymptomatic
patients with chronic ischemic heart disease receiving background atenolol
50mg/d on exercise test parameters
 574 patients were analysed
 n= 217 receiving TMZ 70 mg/day;
 n= 233 receiving TMZ 140 mg/day;
 n= 124 placebo group
 assessed the efficacy of the two doses of TMZ on
 total exercise duration (TED)
 time to 1-mm ST segment depression (T1).

15.  Amongst patients with limiting angina during exercise test,
both doses of TMZ significantly improved both T1 and TED.
 Both doses of TMZ significantly increased TED (p=0.0044 and
p=0.0338 for TMZ 140 mg/d and TMZ 70 mg/d, respectively).
 A greater TED improvement was observed in TMZ 140 mg/d
than in TMZ 70 mg/d, although the difference was not
significant.
 No difference in serious adverse events was noted between
TMZ and placebo

16. TACT: Trimetazidine in Angina
Combination Therapy-2005
 randomized, placebo-controlled study
 Assessed the efficacy and acceptability of trimetazidine
(TMZ) in combination with hemodynamic agents (beta-
blockers or long-acting nitrates) in 177 stable angina
patients
 stable angina patients resistant to nitrates or beta-blockers
 Randomised to TMZ (20 mg t.i.d., n = 90) or placebo (Pbo
t.i.d., n = 87) orally.
 A final exercise test was performed after 12 weeks of
treatment (W12).

17.  The mean number of decreased from in the TMZ
group versus in the Pbo group), decreased in the
TMZ group in the Pbo group (NS)
TMZ group Pbo
exercise test
duration
417.7 ± 14.2 (W0) to
506.8 ± 17.7
seconds
435.3 ± 14.8 (W0) to
458.9 ± 16.2
seconds
P < 0.05
Time to 1-mm STD 389.0 ± 15.3 (W0) to
479.6 ± 18.6
seconds (W12)
411.8 ± 15.2 (W0) to
428.5 ± 17.3
seconds (W12
P < 0.05).
Time to onset of
anginal pain
417.0 ± 16.9 (W0) to
517.3 ± 21.0
seconds (W12)
415.1 ± 16.5 (W0) to
436.4 ± 18.5
seconds (W12)
P < 0.005).
anginal attacks per
week
5.6 ± 0.6 to 2.7 ± 0.5 6.8 ± 0.7 to 5.1 ± 0.7 (P < 0.05
mean consumption
short-acting nitrates
per week
from 5.2 ± 0.9 to 2.8
± 0.8
versus 5.5 ± 0.8 to
4.1 ± 0.9
NS

18. Meta-analyses
 In a meta-analysis of 23 trials with 1378 patients with stable
angina conducted by Ciapponi et al. TMZ reduced
 the number of weekly angina attacks (P < 0.0001)
 weekly nitroglycerin tablet consumption (P < 0.0001)
 improved exercise time to 1 mm ST-segment depression on the
exercise test (P = 0.0002)
 In the largest meta-analysis, conducted by Danchin et al.
evaluating 218 trials with a total 19 028 patients, TMZ
significantly improved
 exercise tolerance
 weekly angina episodes
 use of short-acting nitrates

20. Aim
 To assess the long-term potential benefits and
safety of trimetazidine added to standard evidence-
based medical treatment in patients who had a
recent successful PCI.

21. Study Design And Participants
 Randomised, double-blind, placebo-controlled,
parallel group, event-driven, international,
multicentre study
 Patients with angina who have had recent
successful PCI at 365 centres in 27 countries across
Europe, South America, Asia, and north Africa were
included in the study

22. Inclusion criteria
 Patients (women or men ≥21 years old and <85 years old of any
ethnic origin)
 Presenting with a single or multivessel CAD and having undergone
PCI for at least one stenosis to either a native coronary artery or a
coronary graft where the PCI fell into any of the following categories:
 (i) indicated because of angina pectoris occurring either in the
context of stable angina (elective PCI) or in the context of an acute
presentation, such as unstable angina/non–ST-segment elevation
myocardial infarction (NSTEMI), but excluding ST-segment elevation
myocardial infarction (STEMI)
 (ii) achieved by stent implantation or by other acceptable
interventional (nonsurgical) means
 (iii) successful as planned by the operator and with no further
revascularization (either percutaneous or surgical) planned
 (iv) uncomplicated, such that the patient’s discharge was not delayed
because of a cardiac or cerebrovascular problem

23. Randomisation and masking
 A balanced allocation ratio was used for randomisation.
 Patients were allocated to either trimetazidine or placebo at inclusion.
 Randomisation was stratified by both country and type of index PCI (elective or
urgent).
 The allocation sequence was generated by the funder’s statistician through
validated in-house application software; access was restricted to people
responsible for the study therapeutic units production until database lock.
 These people had no involvement in the rest of the trial.
 Study investigators, including all research teams and patients, were masked to
treatment allocation.

24. Procedure
 Up to 1 month after PCI, patients were assigned to either
trimetazidine modified-release 35 mg twice daily (or once
daily for patients with moderate renal failure) or
matching placebo.
 These were given in addition to routine post-PCI
treatment, including secondary prevention therapy,
according to country specific guidelines.
 Treating clinicians were free to prescribe background
antianginal therapy with the exception of perhexiline,
ranolazine, and open-label trimetazidine.

25.  Patients were assessed at trial visits at
 1, 3, and 6 months after randomisation
 thereafter at 6-month intervals.
 These visits consisted of
 clinical examinations
 reporting of concomitant treatments
 reporting of efficacy and safety events
 Canadian Cardiovascular Society (CCS) classification of
angina symptoms

26. Primary end points
 The primary efficacy end point of ATPCI was the time to first
occurrence of an event in the composite of:
 (i) cardiac death
 (ii) hospitalization for a cardiac event
 (iii) recurrent or persistent angina leading to adding, switching, or
increasing the dose of one of the evidence-based antianginal therapies
 iv) recurrent or persistent angina, leading to performance of a coronary
angiography
 All of which were reviewed by an independent adjudication committee.
 The primary safety end point was the incidence of serious emergency
adverse events (in all visits) with trimetazidine as compared with
placebo.

27.  The secondary end points were the time to first
occurrence of each of the separate four components
of the primary end point, with the addition of
evidence of ischemia (documented by stress
imaging and leading to adding, switching, or
increasing the dose of one of the evidence-based
antianginal therapies).

28.  Other secondary endpoints were
 all cause mortality
 occurrence of an event, either taken individually or as a
composite, among the components of the primary and the main
secondary composite endpoints
 hospitalisation for myocardial infarction; hospitalisation for
myocardial infarction or occurence of cardiac death
 hospitalisation for non-fatal myocardial infarction
 hospitalisation for ischaemic chest pain
 hospitalisation for heart failure
 any coronary revascularisation
 and repeat coronary revascularisation in response to angina.
 All of these outcomes were analysed on a time-to-first-event
basis

29.  The primary safety endpoint was any serious
adverse event.
 Neurological symptoms (including Parkinson’s
syndrome, disorientation, hallucination, and
convulsion), coagulation disorders (including non-
traumatic haemorrhages), thrombocytopenia,
agranulocytosis, falls, arterial hypotension, serious
skin disorders, and hepatic disorders were
prespecified events of interest

30. Statistical analysis
 It was calculated that 1363 primary efficacy outcome
events would provide the trial with a power of 85% to
detect a hazard ratio (HR) of 0·85 for the primary
endpoint with trimetazidine compared with placebo, at
a significance level of 5%.
 With an expected annual event incidence of 10% in the
placebo group, it was estimated that the enrolment of
about 5800 patients would provide the required
number of primary events with an average follow-up
period of about 36 months, and an annual study
withdrawal rate of 2%

31.  The type I error rate was set at 5%.
 Prespecified subgroup analyses were done
according to the nature of the index PCI.
 Similar analyses were done for other time-to-event
secondary endpoints.

32. Results
 From Sept 17, 2014, to June 15, 2016, 6369 patients
were assessed for eligibility.
 6007 patients were eligible and randomly assigned
to either trimetazidine (n=2998) or placebo
(n=3009).
 The final visit occurred on Dec 13, 2019.

34.  Because the primary efficacy endpoint event rate
was lower than expected, the executive committee
decided to prolong the follow-up by 12 months.
 No comparative interim analysis was performed.
 Median follow-up duration was 47∙5 months (IQR
42∙3–53∙3)

36.  The two groups were well balanced with respect to
baseline characteristics
 3490 patients had had an elective PCI and 2517 had had an
urgent PCI
 The mean age was 60∙9 years (SD 9·7)
 1123 (18·7%) were 70 years or older,
 4624 (77·0%) were men
 5124 (85·3%) were white.
 3281 (54·6%) of the patients had single-vessel disease.
 2065 (34·4%) patients had incomplete revascularisation
(ie, a 50% or more diameter stenosis in one or more major
epicar dial coronary arteries after PCI).

40.  5824 (97·0%) patients were on dual antiplatelet treatment
(aspirin+P2Y12 inhibitor)
 5804 (96·6%) were on lipid-lowering agents, and
 4940 (82·2%) were on renin–angiotensin inhibitors
(angiotensin-converting enzyme inhibitors, angiotensin-
receptor blockers, or aldosterone antagonists)
 5038 (83·9%) patients received β blockers
 1665 (27·6%) received calcium channel blockers, with an
average of 1∙3 antianginal agents per patient, not including
the study treatment.

41.  The frequencies of primary composite endpoint
events were similar between trimetazidine (700
[23·3%] patients) and placebo (714 [23·7%]; HR
0∙98; [95% CI 0∙88–1∙09], p=0∙73), as were the
frequencies of the components analysed
individually
 Similar results were obtained in the elective and
urgent PCI groups

44.  The frequencies of major secondary endpoint events
were similar between the two treatment groups (706
[23·5%] in the trimetazidine group and 723 [24·0%] in
the placebo group
 There were no differences between the two groups in
the reasons for hospitalisation for cardiac events
 Neither all-cause mortality nor the composite of
hospital admission for myocardial infarction (fatal or
non-fatal) or cardiac death, or any of the other
secondary endpoints were modified by assigned
treatment

45.  Subgroups analysis showed no significant difference between
groups for the primary endpoint
 The proportion of patients with CCS class 2 or higher decreased
throughout the study in both the trimetazidine and placebo groups
 538 (18·0%) of 2986 patients in the trimetazidine group versus
545 (18·2%) of 2998 in the placebo group had CCS class 2 or higher
at month 1,
 442 (15·1%) of 2930 versus 414 (14·1%) of 2930 at month 12,
 and 294 (9·8%) of 2992 versus 300 (10·0%) of 3004 at the end of
the study

49.  Primary safety endpoint (serious adverse events)
occurred in 1219 (40·9%) of 2983 patients in the
trimetazidine group and in 1230 (41·1%) of 2990
in the placebo group
 Frequencies of serious adverse events remained
similar between the treatment groups when split by
system organ class

50.  The adjudicated adverse events of interest were no
more frequent in the trimetazidine group than the
placebo group
 The frequency of neurological symptoms was similar
between the trimetazidine group and the placebo group.
 There were no differences between the groups in the
incidence of coagulation disorders (including non-
traumatic haemorrhages), thrombocytopenia,
agranulocytosis, falls, arterial hypotension, hepatic
disorders, or serious skin disorders.

52. Discussion
 This study investigated the prophylactic use of
trimetazidine, added to background guidelines-
based medical treatment in patients with coronary
artery disease, who had had a successful PCI for
stable angina, unstable angina, or NSTEMI.
Trimetazidine did not reduce the risk of cardiac
events compared with placebo

53.  In this study, the successful elective and urgent PCI
procedures had better outcomes than was predicted, such
that follow-up was prolonged by 12 months to obtain a
sufficient number of events
 Cardiac death occurred in 143 (2·4%) of 6007 patients and
non-fatal myocardial infarction in 244 (4·1%) patients over a
median follow-up of 3∙96 years
 A recent meta-analysis of 19 PCI trials, in rate with a second-
generation drug-eluting stent implantation involving 25 032
patients, reported a 4% cardiac death after a median follow-
up of 4∙1 years and 5% for non-fatal myocardial infarction.

54.  The ATPCI study included
 younger patients with a low atherosclerotic burden (about half had single-vessel
disease),
 only after the investigator was reassured that the procedure had been successfully
completed as planned without complications.
 Most patients had preserved ejection fraction.
 preventive therapy use was high
 outcome of the disease has probably improved over time, in parallel with general
lifestyle improvements, particularly for patients with coronary artery disease.
 Adherence to contemporary guideline recommended medical therapy has also
increased, especially in clinical trials.
 The technology and materials for PCI also have greatly improved.

55.  Notably, a possible association between
trimetazidine and Parkinsonism has been
previously described.
 In this study, the occurrence of neurological
symptoms such as Parkinson’s disease, atypical
Parkinsonism, or drug-induced Parkinsonism, were
similar in the placebo and trimetazidine arms.

56. Limitations
 Patients were only enrolled after a successful PCI
 STEMI pt were excluded
 presence of angina immediately after PCI before
enrolment was not recorded

57. Take home message
 The long-term outcome of patients who have had successful PCI for stable angina or
non-ST segment elevation acute coronary syndrome receiving contemporary
treatments is better than was predicted at the start of this study.
 The ATPCI study showed that the prophylactic use of trimetazidine added to
guideline recommended medical therapy did not improve the outcome of patients
after a successful elective or urgent PCI and no safety issues were identified.
 Trimetazidine
 is different from the classical antiischaemic or antianginal drugs.
 Its action is independent of heart rate or blood pressure reduction, but improves
cardiac energy metabolism, favouring glucose over free fatty acid use.
 does not prevent ischaemia from developing but prevents some of the consequences
of ischaemia.

58.  Thank you