• Users Online: 455
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
CURRICULUM IN CARDIOLOGY - JOURNAL CLUB
Year : 2017  |  Volume : 3  |  Issue : 3  |  Page : 160-162

Objective randomized blinded investigation with optimal medical therapy of angioplasty in stable angina


1 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
2 Senior Resident Cardiology, AIIMS, Delhi, India

Date of Web Publication1-Feb-2018

Correspondence Address:
Dr. Arvind Dambalkar
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_57_17

Rights and Permissions

How to cite this article:
Dambalkar A, Singh AI. Objective randomized blinded investigation with optimal medical therapy of angioplasty in stable angina. J Pract Cardiovasc Sci 2017;3:160-2

How to cite this URL:
Dambalkar A, Singh AI. Objective randomized blinded investigation with optimal medical therapy of angioplasty in stable angina. J Pract Cardiovasc Sci [serial online] 2017 [cited 2022 Dec 3];3:160-2. Available from: https://www.j-pcs.org/text.asp?2017/3/3/160/224491



Citation: Al-Lamee R, Thompson D, Dehbi HM, Sen S, Tang K, Davies J, et al. Percutaneous coronary intervention in stable angina (ORBITA): A double-blind, randomised controlled trial. Lancet 2017. pii: S0140-6736(17)32714-9.[1]


  Introduction Top


  • More than 500,000 percutaneous coronary interventions (PCIs) are done annually worldwide for the relief of angina
  • In India, total coronary interventions in 2014 – 248,152 (2014 NIC registry)
  • The Coronary Artery Surgery Study demonstrated that coronary-artery bypass surgery reduced neither mortality nor subsequent myocardial infarctions (MIs) in patients with stable single-vessel disease [2]
  • In 1992, Veterans Affairs ACME investigators conducted a randomized controlled trial which concluded that in patients with single-vessel coronary artery disease, percutaneous transluminal coronary angioplasty offers earlier and more complete relief of angina than medical therapy and is associated with better performance on the exercise test [3]
  • COURAGE [4] established that there was no difference in survival, revascularization or freedom from death, MI, or stroke compared to optimal medical treatment (OMT); however, the health status (symptoms, function, and quality of life as assessed by the Seattle Angina Questionnaire) was worse in OMT patients
  • Criticisms


    • None of the abovementioned trials were blinded. In the absence of blinding, the effect size of PCI on symptomatic endpoints can be overestimated
    • None of the trials had a placebo control arm; placebo effects are known to be larger for invasive than noninvasive treatments.


Recently, ORBITA trial was done to assess the efficacy of PCI compared with a sham placebo procedure for angina relief among patients with stable angina.

Study design

  • Blinded, multicenter randomized trial done at five study sites in the UK
  • Funded by grants from NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, and Imperial College Healthcare Charity. Coronary pressure wires were supplied by Philips Volcano
  • Total number of enrollees: 200
  • Duration of follow-up: 6 weeks.


Inclusion criteria

  • Age 18–85 years
  • Stable angina/angina equivalent
  • At least one angiographically significant lesion (≥70%) in a single vessel that was clinically appropriate for PCI.


Exclusion criteria

  • Angiographic stenosis ≥50% in nontarget vessel
  • Acute coronary syndrome within the last 6 months
  • Previous coronary artery bypass graft surgery
  • Left main stem disease
  • Contraindications to PCI or drug-eluting stent (DES) implantation
  • Heavily calcified or tortuous vessels precluding pressure wire insertion
  • Known severe valvular disease
  • Known severe left ventricular (LV) systolic impairment
  • Moderate-to-severe pulmonary hypertension
  • Chronic total occlusion in target vessel
  • Life expectancy <2 years
  • Pregnancy
  • Age <18 years or >85 years
  • Inability to give consent.


Study objectives

Primary endpoint

  • Difference in exercise time increment between the two arms.


Secondary endpoints

  • Peak VO2
  • Exercise time to development of angina
  • Exercise time to ST depression of 1 mm
  • Angina severity as measured by CCS class
  • Angina score a measured by Seattle Angina Questionnaire score
  • Quality of life as measured by EQ-5D questionnaire
  • Duke treadmill score
  • Dobutamine stress echo wall motion index.



  Methods Top


  • Patients were randomized in a 1:1 fashion to either PCI or a placebo sham procedure
  • After enrollment, patients were optimized on medical therapy for 6 weeks
  • Coronary angiography was done through a radial or femoral arterial approach with auditory isolation achieved by placing over-the-ear headphones playing music on the patient throughout the procedure
  • In all patients, invasive physiological assessment of fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) was done. The operator was blinded to these values (iFR/FFR) and therefore did not use them to guide treatment
  • Randomization was done after this physiological assessment
  • For patients allocated to PCI, DESs were used to treat all lesions that were deemed to be angiographically significant, with a mandate to achieve angiographic complete revascularization. After PCI, iFR and FFR were measured again
  • In the placebo group, patients were kept sedated for at least 15 min on the catheter laboratory table, and the coronary catheters were withdrawn with no intervention having been done.


Statistics

  • All analyses were done on the basis of the intention-to-treat principle
  • P < 0·05 was deemed to be significant
  • To detect an effect size of 30 s with 80% power, required 200 randomized patients
  • Continuous endpoints were analyzed with the two-sample t-test of the difference between groups and were reported as the difference in mean change between study groups with 95% CIs and P values
  • Angina severity between study groups was compared with the Chi-square test of independence at enrollment, before randomization, and follow-up.



  Results Top


Patient characteristics

  • Mean patient age: 66 years
  • Percentage female: 27%
  • Previous PCI: 13%
  • LV ejection fraction normal: 92%
  • Canadian cardiovascular society angina severity grading Class: I (3%), II (59%), III (39%)
  • Angina duration: 9 months
  • Vessel involved: left anterior descending (69%)
  • Median area stenosis by quantitative coronary angiography: 85%
  • Mean exercise duration was 8 min and 48 s in PCI group versus 8 min 10 s before randomization
  • Median baseline FFR value: 0.72; median post-PCI FFR value: 0.9
  • There was no evidence of unblinding at either time point.


Primary outcome

Change in exercise time from baseline for PCI versus sham was 28.4 versus 11.8 s, P = 0.2.

Secondary outcomes

  • There was no significant differences between groups in the change from prerandomization to follow-up in Seattle physical limitation score (2.4, 95% confidence interval [CI] −3.5–8.3, P = 0.420), Seattle angina frequency (4.4, −3.3–12.0, P = 0.260), and Seattle angina stability score (0.9, −8.4–10.2, P = 0.851)
  • There was also no significant difference between the groups in the change in EQ-5D-5 L (0.00, 95% CI − 0.04–0.04, P = 0.994)
  • Change in Duke treadmill score from baseline: 1.22 versus 0.1, P = 0.1
  • Dobutamine stress echocardiography peak stress wall motion score index improved more with PCI than with placebo (−0.09, 95% CI − 0.15–−0.04, P = 0.0011).


Adverse events

None of the patients died. There were three periprocedural major bleeding events (two with PCI and one with placebo). In four patients in the placebo group, PCI was needed for a pressure-wire-related complication. During the follow-up phase, in the placebo group, one patient developed an acute coronary syndrome, and two patients had major bleeding on dual antiplatelet therapy.


  Discussion Top


  • ORBITA's findings show that placebo-controlled randomized trials remain necessary even for a therapy, thought to be so beneficial that a placebo-controlled trial is deemed unnecessary and perhaps unethical
  • The relationship between angiographic significant stenosis in epicardial vessel and angina, though seems direct, is affected by the status of microvasculature
  • The first blinded, sham placebo-controlled trial of PCI for stable angina
  • ORBITA only investigated PCI for stable angina, and the results have no implications for patients undergoing PCI for acute coronary syndrome, including ST-elevation MI for which morbidity and mortality advantages from PCI have been proven.


Positive points

  • The study highlighted the benefit of optimal medical therapy in patients with stable angina with single vessel disease. The medical therapy optimization phase was intentionally intensive consisting of one to three telephone consultations per week with a consultant cardiologist supported by home blood pressure and heart rate measurements
  • The potential magnitude of sham controls was realized in this study which provides a window for exploration of the complex relationship between anatomy, physiology, and symptoms avoiding the illusionary improvements with invasive procedures
  • In the study, PCI did not improve exercise time beyond the effect of the placebo in patients on OMT despite the patients having ischemic symptoms, severe coronary stenosis both anatomically (84.4% area reduction) and hemodynamically (on-treatment FFR 0.69 and iFR 0.76) similar to the means of 0.71 in FAME and 0.68 in FAME-2.


Controversy

  • The trial appears too small in size to address a question of this magnitude in spite of being powered for exercise treadmill-based endpoints
  • As a result of the limited duration of ORBITA, it cannot address long-term MI and mortality endpoints
  • The baseline mean Duke treadmill score, exercise duration (8 min and 48 s in PCI group vs 8 min 10 s), peak O2 uptake at baseline was 25 ml/kg/min, near normal for the age group were reflective of low risk stable angina patients who would not benefit much with revascularization in terms of mortality or quality of life
  • The SAQ angina frequency score was 79 and 75, thereby meaning approximately monthly angina frequency. The follow-up of these patients for 6 weeks might be insufficient to detect significant change in angina frequency
  • All the patients had single vessel disease and the majority of patients had a good LV function. Hence, the results of the study cannot be extrapolated to patients with multivessel disease and LV dysfunction
  • Not all patients would prefer taking multiple antianginal agents forever. Some patients might prefer an invasive procedure for the potential to need fewer medications
  • The trial was designed to achieve good quality background antianginal therapy. Achieving this required several consultations per week with a consultant cardiologist which might not be possible in real world scenarios
  • Any trial using exercise testing as an endpoint might experience a training effect which could have minimized the benefit of PCI
  • It is unlikely that the nontarget vessels in the patients were entirely normal. Ischemia from a nontarget vessel or from microvascular disease could have contributed to angina that the PCI procedure would not have improved.



  Conclusion Top


  • The sham control study is a powerful tool for evaluation of a procedure-oriented trials, where a procedural placebo effect is balanced out
  • Optimal medical therapy fares well against PCI in terms of quality of life in patients with stable angina with a single vessel disease
  • PCI significantly reduced ischemic burden as assessed by stress echo, the clinical significance of which would be more clear with results of ISCHEMIA trial.[5]


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Al-Lamee R, Thompson D, Dehbi HM, Sen S, Tang K, Davies J, et al. Percutaneous coronary intervention in stable angina (ORBITA): A double-blind, randomised controlled trial. Lancet 2017. pii: S0140-6736(17)32714-9.  Back to cited text no. 1
    
2.
CASS Principal Investigators and Their Associates. Myocardial infarction and mortality in the coronary artery surgery study (CASS) randomized trial. N Engl J Med 1984;310:750-8.  Back to cited text no. 2
[PUBMED]    
3.
Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. Veterans affairs ACME investigators. N Engl J Med 1992;326:10-6.  Back to cited text no. 3
[PUBMED]    
4.
Spertus JA, Maron DJ, Cohen DJ, Kolm P, Hartigan P, Weintraub WS, et al. Frequency, predictors, and consequences of crossing over to revascularization within 12 months of randomization to optimal medical therapy in the clinical outcomes utilizing revascularization and aggressive drug evaluation (COURAGE) trial. Circ Cardiovasc Qual Outcomes 2013;6:409-18.  Back to cited text no. 4
[PUBMED]    
5.
ISCHEMIA Trial (Executive Summary). April, 2014. Available from: http://www.ischemiatrial.org. [Last accessed on 2017 Nov 12].  Back to cited text no. 5
    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
  Introduction
  Methods
  Results
  Discussion
  Conclusion
   References

 Article Access Statistics
    Viewed2267    
    Printed108    
    Emailed0    
    PDF Downloaded178    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]