Remote Ischemic Conditioning in Patients with Acute Coronary Syndromes: A Systematic Review with Meta-Analysis and Trial Sequential Analysis

Figures & data

Table 1 Specification of the Research Question Applying a PICO (Population, Intervention, Comparison and Outcome) Model

Population	Intervention	Comparison	Outcomes
Adults (≥18 years) presenting with acute coronary syndromes (STEMI, NSTEMI or S/UA), treated with percutaneous coronary intervention	Remote ischemic conditioning; cycles of blood pressure cuff inflation and deflation applied before PCI (pre-conditioning), during PCI (per-conditioning) or after PCI (post-conditioning)	PCI with no conditioning	Mortality, myocardial infarction, congestive heart failure

Notes: Subgroups were stratified by population (STEMI versus NSTEMI or S/UA) and intervention (pre-, per-, post-conditioning).

Abbreviations: STEMI, ST-segment elevation myocardial infarction; NSTEMI, no ST-segment elevation myocardial infarction; S/UA, stable/unstable angina pectoris; PCI, percutaneous coronary intervention.

Figure 1 PRISMA flow diagram of study selection from the literature searches for the systematic review of randomized clinical trials (RCTs) investigating the efficacy of remote ischemic conditioning (RIC) in acute coronary syndromes (ACS) patients undergoing percutaneous coronary intervention (PCI).

Note: Copied from Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–269. doi:10.7326/0003-4819-151-4-200908180-00135.³¹

Table 2 Characteristics of the 13 Trials Comparing Remote Ischemic Conditioning (RIC) versus No Conditioning (Controls) in Acute Coronary Syndromes (ACS) Patients Undergoing Percutaneous Coronary Intervention (PCI)

First Author	Year	Country	RIC/controls (n/n)	Age^a (mean)	Men (%)	Hypertension (%)	Diabetes (%)	Smokers (%)	Followup^a (mean)	PatientYears^b
Carrasco-Chinchilla^Citation36	2013	ES	118/114	64.6	68.1	75.6	42.1	66.0	1.0	232.00
Crimi^Citation3	2013	IT	48/48	58.4	87.5	52.1	11.5	47.9	1.0	96.00
Sloth^Citation14	2014	DK	126/125	62.5	75.7	31.1	9	56.2	3.8	953.80
Yamanaka^Citation4	2015	JP	47/47	67.0	74.5	63.8	33.0	53.3	0.08	7.52
Liu^Citation5	2016	CN	59/60	62.4	79.0	42.9	20.2	42.9	1.0	119.00
Lavic^Citation34	2016	Canada	119/118	63.8	72.6	70.0	32.9	-	1.7	402.90
Lavic^Citation34	2016	Canada	119/118	64.4	73.8	69.6	30.0	-	1.7	402.90
Verouhis^Citation35	2016	SE	47/46	61.0	94.6	22.6	8.6	37.6	0.08	7.44
Zhou^Citation6	2017	CN	72/58	59.7	35.4	78.5	49.2	56.9	0.5	65.00
Elbadawi^Citation33	2017	USA	30/30	51.6	83.3	33.3	41.7	70.0	0.5	30.00
Qian^Citation32	2018	CN	37/34	56.4	53.5	54.9	11.3	32.4	0.5	35.50
Gaspar^Citation13	2018	PT	231/217	60.0	80.1	49.1	27.9	58.9	2.1	940.80
Hausenloy^Citation15	2019	UK, DK, ES, RS	2546/2569	63.5	76.8	41.4	11.1	39.3	1.0	5115.00

Notes: ^ayears, ^bpatients-years = (total number of patients × mean follow-up time in years), ^cstudy with two intervention arms (RIC with arm cuff and thigh cuff).

Abbreviations: ES, Spain; IT, Italy; PT, Portugal; UK, United Kingdom; DK, Denmark; RS, Serbia; CN, China; SE, Sweden; JP, Japan.

Table 3 Review Authors’ Quality Assessment of the 13 Trials Comparing Remote Ischemic Conditioning (RIC) versus No Conditioning in Acute Coronary Syndromes (ACS) Patients Undergoing Percutaneous Coronary Intervention (PCI)

First Author	Selection Bias		Detection Bias			Attrition Bias	Other bias	Overall Low Risk of Bias	Powered for Clinical Outcomes
	Random Sequence Generation	Allocation Concealment	Blinding of Outcome Assessment			Incomplete Outcome Data	Intention to Treat Analysis
			Mortality	MI	CHF
Carrasco-Chinchilla^Citation36	Yes	Yes	Yes	Yes	-	No	Yes	Yes	No
Crimi ^3	Yes	Yes	Yes	Yes	-	No	Yes	Yes	No
Sloth^Citation14	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	No
Yamanaka^Citation4	Yes	Unclear	Yes	-	Unclear	No	Yes	Nno	No
Liu^Citation5	Yes	Yes	Yes	Yes	Yes	No	Unclear	No	No
Lavia^Citation34	Yes	Unclear	Yes	Yes	-	Yes	Unclear	No	No
Lavia^Citation34	Yes	Unclear	Yes	Yes	-	Yes	Unclear	No	No
Verouhis^Citation35	Yes	Yes	Yes	-	-	No	Unclear	No	No
Zhou^Citation6	Unclear	Unclear	Yes	Yes	-	Yes	Unclear	No	No
Elbadawi^Citation33	Unclear	Unclear	Yes	Yes	-	Yes	Yes	No	No
Qian^Citation32	Unclear	Unclear	Yes	Yes	Unclear	No	Yes	No	No
Gaspar^Citation13	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes
Hausenloy^Citation15	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes

Notes: ^aStudy with two intervention arms (RIC with arm cuff and thigh cuff).

Abbreviations: MI, myocardial infarction; CHF, congestive heart failure.

Figure 2 Forest plot for meta-analysis of randomized clinical trials (RCTs) comparing remote ischemic conditioning (RIC) with no conditioning in acute coronary syndromes (ACS) patients for endpoint; (A) mortality (B) myocardial infarction (C) congestive heart failure.

Notes: Total; amount of person-years, Lavi; study with two intervention arms (RIC with arm cuff and thigh cuff)
Abbreviations: RR, rate ratio; CI, confidence interval.

Figure 3 Funnel plot of the effect of remote ischemic conditioning (RIC) for endpoint (A) mortality (B) myocardial infarction (C) congestive heart failure.

Abbreviations: logrr, log rate ratio; s.e, standard error.

Table 4 Trial Sequential Analysis (TSA) for Power Estimation

A. All Studies
Accrued Information Size (AIS)
Endpoint	RRR (%)	Type-I error (%)	Power (%)	AIS (N)
Mortality	10	5	99	7183
Myocardial infarction	10	5	99	6996
Congestive heart failure	10	5	98	6098
Low Bias Information Size (LBIS)
Endpoint	RRR (%)	Type-I error (%)	Power (%)	LBIS (N)
Mortality	18	5	80	803
Myocardial infarction	14	5	80	1407
Congestive heart failure	26	5	80	340
Low Bias Heterogeneity-Adjusted Information Size (LBHIS)
Endpoint	RRR (%)	Type-I error (%)	Power (%)	LBHIS (N)
Congestive heart failure	26	5	80	487
B. Subgroup of Trials with STEMI Patients
Accrued Information Size (AIS)
Endpoint	RRR (%)	Type-I error (%)	Power (%)	AIS (N)
Mortality	10	5	99	6347
Myocardial infarction	10	5	99	6160
Congestive heart failure	10	5	98	6098
Low Bias Information Size (LBIS)
Endpoint	RRR (%)	Type-I error (%)	Power (%)	LBIS (N)
Mortality	24	5	80	437
Myocardial infarction	17	5	80	854
Congestive heart failure	26	5	80	340
Low Bias Heterogeneity-Adjusted Information Size (LBHIS)
Endpoint	RRR (%)	Type-I error (%)	Power (%)	LBHIS (N)
Mortality	24	5	80	716
Congestive heart failure	26	5	80	487

Abbreviations: RRR, relative risk reduction; N, patients.

Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–269. doi:10.7326/0003-4819-151-4-200908180-0013519622511

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