CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the ORBITA-2 Trial
Table of contents for the The The ORBITA-2 Trial summary:
Feb 28, 2023
A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina
Christopher A. Rajkumar, M.B., B.S., Michael J. Foley, M.B., B.S., Fiyyaz Ahmed-Jushuf, M.B., B.S., Alexandra N. Nowbar, Ph.D., Florentina A. Simader, M.D., John R. Davies, Ph.D., Peter D. O’Kane, M.D., Peter Haworth, M.B., B.S., Helen Routledge, M.D., Tushar Kotecha, Ph.D., Reto Gamma, M.D., Gerald Clesham, Ph.D., et al., for the ORBITA-2 Investigators*
https://www.nejm.org/doi/full/10.1056/NEJMoa2310610
Relevant literature
Relevant Guidelines
2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines
Objectives:
The study was designed to evaluate the efficacy of PCI compared with sham procedure in relieving angina among patients with stable angina not on antianginal medications.
Trial –
- Conducted at 14 sites in the United Kingdom
- 923 patients screened, 439 enrolled to pre-randomization symptom assessment phase, 301 randomly assigned to PCI or placebo between 11/12/2018 to 6/17/2023
Intervention
- Randomly assigned 1:1 to percutaneous intervention or placebo-controlled sham procedure following 2 week symptom assessment phase and cessation of all antianginal meds .
- PCI group (n=151):
- Angiographic and physiological complete revascularization of the target vessels was mandatedPhysiological assessment was performed pre and post procedure to identify the target vessel and to document complete revascularizationIntravascular imaging encouraged, but not requiredIn patients with multivessel disease, all vessels treated during index procedure
- Placebo-controlled sham procedure (n=150):
- Patients remained sedated without any further intervention for 15 minutes
Enrollment Criteria
- Inclusion criteria:
- Considered to be clinically suitable for PCI by the referring heart team
- Patients had angina or symptoms equivalent to angina
- Had anatomic evidence of at least one severe coronary stenosis identified on invasive diagnostic coronary angiography or coronary computed tomographic angiography
- Had evidence of ischemia on the basis of noninvasive imaging or invasive coronary physiological tests
- Exclusion criteria
- Age younger than 18
- Recent acute coronary event (in last 6 months)
- Previous CABG
- Significant left main stem coronary disease
- Chronic total occlusion in target vessel
- Contraindication to PCI or DES implantation, CI to antiplatelet therapy
- Severe valvular disease
- Severe LV systolic impairment < 35%
- Severe respiratory disease
- Life expectancy < 2yrs, pregnancy, inability to consent
Outcomes
- Primary Endpoint: Angina symptom score, an ordinal clinical outcome scale of health status associated with angina
- Angina symptom score: calculated on basis of number of angina episodes reported on a given day and the number of units of antianginal medication prescribed on that day
- Higher number of episodes of angina or more antianginal medications led to a higher score
- A patient with no episodes of angina and received no antianginal medications on a day had a score of 0
- Also incorporated occurrence of unblinding owing to unacceptable angina requiring coronary angiography, occurrence of ACS, and death (which would result in the maximum score of 79).
- Angina symptom score: calculated on basis of number of angina episodes reported on a given day and the number of units of antianginal medication prescribed on that day
- Secondary Endpoints: Frequency of angina as reported by the patient with the use of smartphone application, initiation and/or subsequent titration of antianginal medications, treadmill exercise time, physician assessed severity of angina (according to CCS class), frequency of angina, physical limitation, angina stability, freedom from angina, quality of life, and stress echo score.
Statistical Analysis
- Primary endpoint: analyzed by means of ordinal analysis of covariance, uses a cumulative probability model that does not impose distribution assumptions on the outcome
- If daily symptoms were not available, the last entered value was used as final follow-up value unless unblinding had occurred due to unacceptable angina or ACS or death
- Freedom from angina was assessed using logistic regression
- Secondary endpoint: analyzed by means of ordinal analysis of covariance technique for ordinal secondary endpoint, CCS class; for analysis of freedom from angina, a logistic-regression model was used; for the other secondary endpoints, an ordinary least-squares model was used
- During the 2019 coronavirus pandemic, hospital research visits for treadmill exercise tests and echocardiography were suspended while national restrictions were in place
Baseline Characteristics
- 301 patients underwent randomization, 151 patients to the PCI group and 150 patients to the placebo group
- Mean age of patients was 64 +/- 9 years; and 79% were male
- At time enrollment, 290 had angina or CCS severity class II or III
- Median number of antianginal agents prescribed for patients prior to enrollment was 1, equivalent to a median of 2 standardized antianginal units
Procedural Characteristics
- Radial artery access used in 288 pts (96%)
- Invasive physiological assessment performed in a median of 1 vessel per patient
- Ischemic territories: identified via invasive physiological assessment and noninvasive functional testing:
- One territory: 242 pts (80%)
- Two territories: 52 pts (17%)
- Three territories: 7 pts (2%)
- Coronary lesion characteristics:
- Mean % diameter stenosis assessed by quantitative coronary angiography was 61 +/- 18%
- FFR done in 349/383 target vessels (91%), with median FFR of 0.63 (interquartile range 0.49 to 0.75)
- IFR done in 352/383 target vessels (92%), with median IFR of 0.78 (interquartile range 0.55 to 0.87)
- intravascular imaging was performed in 69% of patients in PCI group. Median post-PCI FFR 0.89 and post PCI IFR 0.93
- Complete revascularization occurred in all but 2 patients
Outcomes
Primary Outcome
- Data available for 99.7% o
if the 22,823 patient-days in trial - At 12-week follow up, mean angina symptom score was 2.9 in PCI group and 5.6 in placebo group
- Odds ratio 2.21, 95% CI 1.41 to 3.47, P<0.001
- Mean daily angina frequency was 0.3 episodes in PCI group and 0.7 episodes in placebo group
- Odds ratio 3.44, 95% CI 2.00 to 5.91
- Mean daily use of antianginal medication was 0.2 in PCI group and 0.3 in placebo group
- Odds radio 1.21, 95% CI 0.70 to 2.10
Secondary Endpoint
Adverse Events
| Adverse event | PCI group (# of pts) | Placebo group (# of pts) |
| Unblinding from unacceptable angina | 0 | 1 |
| ACS | 4 | 6 |
| Death | 0 | 0 |
| Periprocedural MI (Type 4a) | 4 | 0 |
| Spontaneous MI (Type 1) | 0 | 6 |
| Stroke | 2 | 0 |
| Pressure wire complications | 1 | 2 |
- See comparison of serious adverse events above between two groups
- In placebo group, there were 2 major periprocedural bleeding events and 2 spontaneous bleeding events in 4 patients who were receiving DAPT
- The trial was designed to determine the effect of PCI alone in patients with stable angina and evidence of ischemia.
- The study ultimately found that PCI as a monotherapy in patients with stable angina resulted in lower angina symptom score than a sham procedure.
- The trial used a new end point, the angina symptom score with the use of the smartphone app, which was patient centered and minimized recall bias and maximized data completeness. A smartphone application was utilized by patients to log daily symptoms, including the frequency of angina episodes and their severity. This method simplified data collection and evaluation, offering valuable insights into the symptoms of stable angina. Furthermore, it provided a practical means of monitoring patient activity and optimizing the algorithms used to prescribe antianginal medications
- “Perhaps for angina relief, the first therapy administered – either antianginal medication or an antianginal procedure, such as PCI – has the greatest chance of efficacy.”
- Limitations & Considerations
- Duration of follow up was only 12 weeks; daily data showed effect of PCI was immediate and sustained
- However, despite decades of technical advances in PCI, including the introduction of stents, the effect of PCI on treadmill exercise time in the blinded ORBITA-2 trial was still 37 seconds less than the 96-second effect attributed to balloon angioplasty in the unblinded Angioplasty Compared to Medicine (ACME) trial that was conducted three decades ago. The effect of PCI as monotherapy was a 59.5-second difference in the tread- mill exercise time as compared with placebo, which was similar to the 48 to 55 seconds achieved with a full-dose single antianginal medication.
- Trial required stopping antianginal medications, which is against guideline recommendations; yet this allowed PCI to be tested as antianginal monotherapy
- Withdrawal of antianginal medication may have led to unmeasured behavioral changes
- Use of nitroglycerin spray was not included in calculation of angina symptom score
- 80% of patients had ischemia in a single territory only
- Smartphone application was available in English only
- Al-Lamee R, Thompson D, Dehbi HM, Sen S, Tang K, Davies J, Keeble T, Mielewczik M, Kaprielian R, Malik IS, Nijjer SS, Petraco R, Cook C, Ahmad Y, Howard J, Baker C, Sharp A, Gerber R, Talwar S, Assomull R, Mayet J, Wensel R, Collier D, Shun-Shin M, Thom SA, Davies JE, Francis DP; ORBITA investigators. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet. 2018 Jan 6;391(10115):31-40. doi: 10.1016/S0140-6736(17)32714-9. Epub 2017 Nov 2. Erratum in: Lancet. 2018 Jan 6;391(10115):30. PMID: 29103656.
- Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16. doi: 10.1056/NEJMoa070829. Epub 2007 Mar 26. PMID: 17387127.
- Maron DJ, Hochman JS, Reynolds HR, Bangalore S, O’Brien SM, Boden WE, Chaitman BR, Senior R, López-Sendón J, Alexander KP, Lopes RD, Shaw LJ, Berger JS, Newman JD, Sidhu MS, Goodman SG, Ruzyllo W, Gosselin G, Maggioni AP, White HD, Bhargava B, Min JK, Mancini GBJ, Berman DS, Picard MH, Kwong RY, Ali ZA, Mark DB, Spertus JA, Krishnan MN, Elghamaz A, Moorthy N, Hueb WA, Demkow M, Mavromatis K, Bockeria O, Peteiro J, Miller TD, Szwed H, Doerr R, Keltai M, Selvanayagam JB, Steg PG, Held C, Kohsaka S, Mavromichalis S, Kirby R, Jeffries NO, Harrell FE Jr, Rockhold FW, Broderick S, Ferguson TB Jr, Williams DO, Harrington RA, Stone GW, Rosenberg Y; ISCHEMIA Research Group. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020 Apr 9;382(15):1395-1407. doi: 10.1056/NEJMoa1915922. Epub 2020 Mar 30. PMID: 32227755; PMCID: PMC7263833.
Summary by: Dr. Cali Clark @CaliRClark and Dr. Hamza Patel @Hamza_Patel123
Visual abstract by: Dr. Christian Andersen @CFAndersenMD
Trial Tweets by: Dr. Rachel Goodman @goodmra1
Moderator of Twitter during CardsJC by: Dr. Hamza Patel @Hamza_Patel123
Promo by: Dr. Rachel Goodman @goodmra1
Under the guidance of House Chief: Dr. Alaa Diab @DrAlaaDiab & Director of CardsJC Dr. Devesh Rai, @DeveshRaiMD
Supported by House Faculty: Dr. Dinu Balanescu @dinubalanescu, Dr. Ty Sweeney @TySweeney6, Dr. Saahil Jumkhawala @saahilaj, and Dr. Eunice Dugan @EuniceDuganMD
