Jc prcamio and protect trial

1. JOURNAL CLUB
15-05-2017

3. INTRODUCTION
• Ventricular tachycardia (VT) is a medical condition,
with an extremely variable clinical presentation, from
being almost asymptomatic to producing cardiac
arrest.
• When the clinical condition of the patient is not
compromised (i.e. blood pressure is maintained and
there are no overt signs of heart failure) VT is usually
referred to as ‘stable’ or ‘well tolerated’.

4. • Stable VT requires prompt intervention for
termination because haemodynamic instability and
deterioration leading to collapse can develop at any
time.
• Termination can be achieved with :
 electrical cardioversion,
 antiarrhythmic medications,
 pacing techniques.

5. • INTRAVENOUS PROCAINAMIDE AND AMIODARONE
are drugs of choice for the treatment of
haemodynamically stable VT with a class II
recommendation.
• Controlled trials with amiodarone have been
performed in various clinical contexts (i.e.
hypotensive VT or cardiac arrest) and procainamide
has been compared with other antiarrhythmic drugs,
but no controlled prospective trial have focused in
comparing these two agents in well tolerated VT.

6. • The PROCAMIO is a multicentre, prospective and
randomized study that compares the safety and
efficacy of intravenous procainamide and
amiodarone in the acute treatment of wide QRS
complex monomorphic tachycardias (presumably VT)
which are haemodynamically well tolerated.
• The majority of wide QRS complex tachycardias presenting at
Emergency Departments are in fact VTs, even if the
haemodynamic tolerance is acceptable. As such, the present
trial refers to ‘WIDE QRS COMPLEX TACHYCARDIA (probably of
ventricular origin)’ rather than to ‘VT’, assuming some
uncertainty in diagnosis.

7. METHODS

8. STUDY DESIGN
• Patients were randomly assigned in an open-labelled
fashion to receive either intravenous procainamide
(single dose 10 mg/kg over 20 min) or intravenous
amiodarone (single dose 5 mg/kg over 20 min) with a
1:1 ratio.
• The study period was 40 min from infusion initiation
(20 min for drug administration and 20 min following
administration).
• There was an observation period of 24 h after the
end of the study period.

9. PATIENT SELECTION
• INCLUSION CRITERIA:
a. Age ≥18 years.
b. Regular wide QRS
tachycardia requiring medical
attention.
c. Rate ≥120 bpm.
d. Good hemodynamic
tolerance (blood pressure
>90, no dyspnea at rest or
angina, no hypoperfusion).
• EXCLUSION CRITERIA:
a. Treatment with either
intravenous amiodarone or
intravenous procainamide
during the previous 24 hours
b. Poor hemodynamic
tolerance requiring urgent
termination
c. Presence of irregular
tachycardia.
d. Tachycardia believed to be
supraventricular tachycardia
e. Contraindications to the
drugs under study.

10. DEFINITIONS AND TREATMENTS
• MAJOR CARDIAC ADVERSE EVENTS were defined as
follows:
1. Clinical signs of peripheral hypoperfusion.
2. Heart failure signs: dyspnoea at rest and/or
orthopnoea associated with signs of pulmonary
congestion (presence or increase of rales and/or
decrease in blood oxygen saturation).
3. Severe hypotension defined as SBP≤70 mmHg if the pre-
treatment SBP was ≤100 mmHg or SBP≤80 mmHg if the
pre-treatment SBP was > 100 mmHg.
4. Tachycardia acceleration of >20 bpm of its mean value.
5. Appearance of fast polymorphic VT.

11. • Drug infusion was stopped by protocol if any of the
following occurred:
(i) termination of the tachycardia during the infusion
period;
(ii) complete administration of the amount of drug
programmed; and
(iii) presence of a major cardiac adverse event.

12. Response to treatment was evaluated as follows:
1. Termination was defined as conversion to the
patient’s known or presumed usual heart rhythm
(e.g. sinus, atrial fibrillation) within the study
period.
2. If the tachycardia terminated within 20 min of drug
infusion initiation and recurred within 20 min
following infusion ending, then the treatment was
considered unsuccessful.

13. STUDY ENDPOINTS
• The primary endpoint of the study was to compare
the incidence of major cardiac adverse events
between both treatments.
• Secondary endpoints were the following:
(i) to compare the efficacy of both drugs in relation to
the acute termination of the tachycardia episode.
(ii) to compare the incidence of total adverse events
during the observation period.

14. SAMPLE SIZE CALCULATIONS
• The sample size calculation for this study had
significant uncertainties.
• There was only one randomized trial with
intravenous procainamide in tolerated VT, with
considerable adverse events and observational
studies with small number of patients had reported
extremely good tolerance of intravenous amiodarone
so it was hypothesized by investigators 20% and 5%
adverse event rate in the procainamide and
amiodarone groups.

15. • Based on these assumptions, 302 patients were
needed to detect a difference of 15% in major
adverse events between both groups
• After nearly 6 years including patients at 2
participating Centres, 74 patients had been
randomized and a trend towards a decrease in
inclusion rate was observed.

16. STATISTICAL ANALYSIS
• Summary statistics for continuous variables was
recorded as means and standard deviations, as well
as medians.
• Comparisons between the two treatment groups
were performed with the Wilcoxon rank-sum test.

17. RESULTS

18. Summary of patient recruitment and results.

20. PRIMARY END POINTS

22. Odds ratio and confidence intervals of adverse events
and tachycardia termination of procainamide patients compared
with amiodarone patients. AE, adverse events; MCAE, major cardiac
adverse events; SP, study period (40 min); OP, observation
period (24 h).

24. SECONDARY END POINTS

25. SUBGROUP ANALYSIS IN PATIENTS WITH
STRUCTURAL HEART DISEASE

26. DISCUSSION

27. • This study shows for the first time in a randomized controlled
trial that when iv procainamide and amiodarone, at usual
clinical doses, are compared for the acute treatment of
spontaneous episodes of well-tolerated wide QRS complex
tachycardias, presumably VT:
 Procainamide is associated with less major cardiac adverse
events;
 Procainamide is more efficacious in terminating the
tachycardia episode;
 Findings equally apply to the subgroup of patients with
structural heart disease.

28. COMPARISON WITH PREVIOUS AVAILABLE
INFORMATION
• In one study which compared procainamide and amiodarone
in a retrospective multicentre historical cohort trial in 90
patients, amiodarone caused severe hypotension requiring
emergency electrical cardioversion in 6%.
• One additional series which used intravenous amiodarone
was a retrospective single cohort analysis which identified 41
patients that received 300 mg, severe hypotension requiring
emergency electrical cardioversion occurred in 7/41 cases
(17%).

29. • But in this study - 41% major cardiac adverse events
in the amiodarone arm.
• Possible explanation can be that in this study
symptoms were prespecified and levels of
hypotension were considered a major event,
whereas in retrospective trials major adverse events
were recognized by the need of electrical
cardioversion.

30. • Retrospective nature of these studies posed
limitations too.
 47 patients (52%) in one study had received another
antiarrhythmic drug and the mean dose was 2.0
mg/kg in patients in whom amiodarone was
ineffective, smaller than the 5 mg/kg used in this
trial;
 In another study the duration of the drug infusion
lasted up to 60 min.

31. • Retrospective nature of these studies posed
limitations too.
 47 patients (52%) in one study had received another
antiarrhythmic drug and the mean dose was 2.0
mg/kg in patients in whom amiodarone was
ineffective, smaller than the 5 mg/kg used in this
trial;
 In another study the duration of the drug infusion
lasted up to 60 min.

32. • The information regarding procainamide for the
acute termination of spontaneous well-tolerated
sustained VT is even more limited.
• In various retrospective studies, major cardiac
adverse events occurred in 13% and 17% while in
this study it was 9%.
• Efficacy was reported in 76% and 57% in
retrospective studies and in 80% in a prospective
study which is consistent with the figure of 67% VT
termination in this study.

33. SELECTED
DOSAGES AND ADMINISTRATION
• The duration of infusion chosen was 20 min.
• Dose of amiodarone was 5 mg/kg infused during 20
min, approximating 300 mg.
• Dose of procainamide 10 mg/kg infused over 20 min.

34. UNEXPECTED FINDINGS?
• Investigators did not expect such a high incidence of major
adverse effects in the amiodarone arm since in the various
studies e.g by Leak et al reported on using a bolus of 150 mg
of amiodarone in 11 critically ill patients and stated that
‘hypotension, cardiac failure and bradyarrhythmias were not
induced by this treatment’.
• Similarly, in severely hypotensive recurrent VT, amiodarone
produced less hypotension than bretilium in another study.
• So investigators hypothesized that if amiodarone was safe in
these very sick patients it was going to be so in the stable
patientwith tolerated VT.

35. • But ,in retrospect, some findings can explain results:
 When the arrhythmia is immediately life threatening, an
antiarrhythmic action can produce such a benefit that
overcomes potential adverse effects.
 In studies performed during resuscitation all patients
had previously received intravenous catecolamines
(adrenaline).
 In critically ill patients most were receiving
catecolamines: these drugs may have counteracted the
hypotensive effects of amiodarone.

36. LIMITATIONS
1. The study included less number of patients that
were required according to sample size calculations
since ;
a. Extension of emergency protocols to treat these
patients on the ambulance; in these protocols only
amiodarone was allowed, precluding participation
in the trial;
b. Fast turnover of medical personnel at emergency
departments.
2. The study design was randomized but not blinded.

37. CONCLUSIONS
• In this randomized prospective study comparing
intravenous procainamide and amiodarone for the
treatment of the acute episode of sustained
monomorphic well-tolerated wide QRS tachycardia
(probably VT), procainamide therapy was associated
with less major cardiac adverse events and a higher
proportion of tachycardia termination within 40 min.

39. • Left anterior descending (LAD) artery supplies 45% to
55% of the left ventricle mass.
• Therefore, patients with LAD disease are thought to
be at higher risk for future cardiovascular events.
• Location of the lesion in the proximal LAD identifies a
higher risk subset of patients in whom the need for,
and the method of, revascularization should be
further discussed.

40. • The data comparing outcomes after revascularization for
proximal LAD versus nonproximal LAD are limited.
• It is not well understood whether the presence of LAD
narrowings requiring revascularization still remains today a
predictor of adverse outcome after percutaneous coronary
intervention (PCI) with a drug-eluting stent (DES) and with
current medical therapy.
• Therefore, investigators aimed to compare long-term
outcomes in patients with or without target lesions in the
proximal LAD.

41. • Investigators analyzed the 4-year outcomes in 8,709
patients who underwent coronary artery stenting in
PROTECT (Patient Related Outcomes with Endeavor
Versus Cypher Stenting Trial), classified according to
lesion location within or outside the proximal LAD.

42. METHODS

43. • PROTECT was an open-label, multicenter trial that
randomized patients undergoing elective, unplanned,
or emergency procedures in native coronary arteries
to the Endeavor zotarolimus-eluting stent (E-ZES) or
the Cypher sirolimus-eluting stent (C-SES)
• The trial involved 196 participating hospitals in 36
countries across 5 continents and was conducted
between May 21, 2007, and December 22, 2008.

44. • The present study included all patients from the
PROTECT trial and compared the cohort of patients
who received at least 1 stent in the proximal LAD
with those who received stents only in nonproximal
LAD locations.
• Proximal LAD was defined according to the Coronary
Artery Surgery Study classification : end of left main
to the first large septal or first diagonal, whichever is
most proximal.

45. PROCEDURE
• Antiplatelet therapy with aspirin and clopidogrel (75 mg) or
another thienopyridine derivative was started 3 days before
the procedure or through a loading dose (clopidogrel 300 to
600 mg or its equivalent for other thienopyridine) for patients
not yet taking these medications.
• During the procedure, 96.7% of patients were treated with
clopidogrel, 0.27% were treated with ticlopidine, and 5.72%
received another antiplatelet/antithrombin drug.
• Post-procedure, aspirin was prescribed indefinitely, and
thienopyridine therapy was prescribed for a minimum of 3
months and up to 12 months , or for longer at the physician’s
discretion.

46. DEFINITIONS
• Major adverse cardiac events (MACE) included all-cause
death, MI (Q-wave and non–Qwave), emergent coronary
artery bypass graft (CABG) surgery, or repeat clinically
indicated target lesion percutaneous or surgical
revascularization.
• Target vessel failure (TVF) included death, target vessel MI (Q-
wave and non–Q-wave), or clinically driven target vessel
revascularization by percutaneous or surgical methods.
• Target lesion failure included death from cardiac causes,
target vessel MI,and target lesion revascularization.

47. • Patients were defined as “complex” if they met at least 1 of
the following clinical or lesion characteristics:
1. Renal insufficiency or failure (defined as creatinine ≥140
mmol/l [1.6 mg/dl]),
2. Left ventricular ejection fraction <30%, the occurrence of an
acuteMI within the previous 72 h,
3. >1 lesion per vessel,
4. ≥2 vessels with stents,
5. Lesion measuring >27 mm,
6. Bifurcation,
7. Bypass grafts,
8. In-stent restenosis,
9. Unprotected left main artery,
10. Lesions with thrombus, or total occlusion (pre-procedure
TIMI [Thrombolysis In Myocardial Infarction] flow grade 0).

48. STATISTICAL ANALYSIS.
• Dichotomous and categorical variables were
reported as counts and percentage.
• Continuous variables were reported as mean SD and
were compared with a 2-sample Student t test.
• All analyses were performed according to the
intention-to-treat principle in the entire enrolled
study population.
• The incidence of clinical outcomes was calculated
using the Kaplan-Meier method and compared using
the log-rank test

49. RESULTS

54. 4-YEAR CUMULATIVE INCIDENCE OF EVENTS STRATIFIED BY
PROXIMAL LAD PATIENTS VERSUS NONPROXIMAL LAD
Based on Kaplan-Meier analysis: (A) major adverse cardiac events (MACE); (B) cardiac death; (C)
target vessel failure (TVF); (D) stent thrombosis; CI ¼ confidence
interval; HR ¼ hazard ratio; LAD ¼ left anterior descending.

55. 4-YEAR CUMULATIVE INCIDENCE OF EVENTS STRATIFIED BY
PROXIMAL LAD PATIENTS VERSUS NONPROXIMAL LAD
Based on Kaplan-Meier analysis: (A) major adverse cardiac events (MACE); (B) cardiac
death; (C) target vessel failure (TVF); (D) stent thrombosis; CI ¼ confidence
interval; HR ¼ hazard ratio; LAD ¼ left anterior descending.

56. DISCUSSION
• In this prospective, multinational, multicenter, randomized
study with DES for single-vessel and multivessel disease, there
was no difference in the rates of death, MACE, or TVF at 4
years according to intervention at a proximal LAD or
nonproximal LAD lesion site.
• The occurrence of the predefined primary endpoint—namely,
stent thrombosis—was not dependent on whether a proximal
LAD or nonproximal LAD site was treated with a DES.
• However, stenting of proximal LAD lesions was associated
with significantly higher rates of MI compared with stenting of
nonproximal LAD lesions.

57. • Results are consistent with an analysis of the
COURAGE (Clinical Outcomes Utilizing
Revascularization and Aggressive DruG Evaluation)
trial, in which disease in the proximal LAD did not
influence death or MI.
• Two relatively large meta-analyses examining the
method of revascularization of the proximal LAD
location have not shown differences in mortality, MI,
or stroke between PCI and CABG

58. • These studies which were followed for 4 and 5 years
respectively used bare metal stents in the PCI arm and
demonstrated a 3-fold increase in recurrent angina and a 5-
fold increase in repeat revascularization with PCI as compared
with CABG.
• In the metaanalysis performed by Kapoor et al. , the 5-year
repeat revascularization rate of patients undergoing CABG for
isolated proximal LAD disease was 7.3% at 5 years, compared
with 33.5% in their PCI arm, whereas in the current study the
TVF rate was 14.8% at 4 years

59. • There are no randomized studies comparing the long-term
outcomes of PCI with CABG for isolated proximal LAD lesions.
• Hannan et al. examined the New York Percutaneous Coronary
Interventions Reporting System for patients who underwent
CABG surgery and received DES for isolated proximal LAD
disease.
• Among 715 of 5,340 patients (13.4%), they reported no
differences in mortality or in a combination of mortality, MI,
and/or stroke using propensity-matched comparisons;
however, CABG patients had significantly lower repeat
revascularization rates.

60. • This study is a post hoc, nonrandomized
comparison; all patients underwent PCI and no
patient underwent CABG.
• Yet investigators found that outcomes in >2,500
patients treated with DES in the proximal LAD were
similar to the outcomes of >6,100 patients with
lesions in other coronary arteries, which currently
are treated ad hoc and do not require further
discussion before decision and intervention

61. STUDY LIMITATIONS
• The comparison of patients with and without a proximal
LAD target lesion was a post hoc analysis.
• Investigators could not exclude the presence of
unmeasured selection bias.
• There are several known and unknown confounders with
significant impact on the endpoints, and even
sophisticated statistical methods cannot eliminate
potential selection bias.
• Investigators do not have information regarding heart
failure and quality of life, as an event in the proximal LAD
may be associated with greater myocardial damage than
one in other coronary artery locations.

62. CONCLUSIONS
• The discussion of how best to treat the patient with a
proximal LAD lesion remains a topic of debate .
• In the present study, investigators found that long-term
outcomes for MACE, mortality, and TVF were similar
regardless of whether the target lesion was in the proximal
LAD or not.
• The nonsignificant interaction between stent type (E-ZES vs.
C-SES) and lesion location (proximal LAD vs. nonproximal LAD)
suggests that these results are independent of stent type.
• This finding may suggest that proximal LAD lesion may not
confer a substantial additional risk in the DES era.

63. • WHAT IS KNOWN? Proximal LAD artery involvement
significantly impacts the recommendations for
revascularization.
• WHAT IS NEW? In patients treated with drug eluting
stents in the proximal LAD, the 4-year event rate was
similar to patients treated in other coronary artery
tree locations.
• WHAT IS NEXT? In the DES era, proximal LAD no
longer confers a different prognosis than other lesion
sites.