Undiscovered pathology of transient scaffolding t1remains a driver of failures in clinical trials

Table 1 The results of post hoc odds-ratio-based sample size calculations for randomized controlled trials and meta-analyses of the bioresorbable vascular scaffold

Trial	No. patients with BVS (ad hoc sample size)	No. patients with metallic DES (ad hoc sample size)	TLF, RR (BVS/DES), P value					ST (definite/probable), RR, P value	ST (definite/probable), rate in BVS patients	Estimated (post hoc) minimal sample size for groups BVS:DES (by TLF), (eOR)	Estimated (post hoc) minimal sample size for groups BVS:DES (by ST), (eOR)	Post-dilation, percent of patients	Full PSP, estimated maximum, percent of patients	Small vessels, QCA RVD (< 2.25 mm), percent of patients
			Total TLF	TLF, rate in BVS patients	Cardiac death	TV-MI	ID-TLR
BVS randomized controlled trials
ABSORB II, by 3 yr[31]	335	166	2.11SP = 0.04	10.5%	0.5 P = 0.40	5.20SP = 0.01	1.65 P = 0.56	Nul P = 0.03	2.8%	324:162 eOR= 2.23	NA	Approximately 60%	NA	NA
ABSORB II, by 4 yr UD[42]	289	139	2.04SP = 0.05	11.1%	NA	NA	NA	NA	3.0%	293:141UD eOR= 2.04	NA	NA	NA	NA
ABSORB III, by 1 yr (13 mo)[2]	1313	677	1.28 P = 0.16	7.8%2	4.12 P = 0.29	1.31 P = 0.18	1.21 P = 0.5	2.08 P = 0.13	1.5%	1236:637 eOR = 1.31	1285:666 eOR= 2.09	66%	66%	19%
ABSORB III, by 2 yr (25 mo)[2]	1322	686	1.39SP = 0.03	11.0%	1.83 P = NS	1.49SP = 0.04	1.23 P = NS	2.38 P = NS	1.9%	1291:669 eOR= 1.45	1215:630 eOR= 2.52	66%	66%	19%
ABSORB III, by 3 yr UD[43]	1322	686	1.31 P = 0.06	13.4%	1.17 P = 0.71	1.47SP = 0.03	1.23 P = 0.27	3.12SP = 0.01	2.3%	1262:655 eOR= 1.23	1375:714UD eOR= 3.16	NA	NA	18.8%
ABSORB IV, by 1 yr (13 mo)[2]	1273 (1500)1	1273 (1500)1	NA	NA	NA	NA	NA	NA	0.5%	NA	NA	83%	83%	4%
ABSORB Japan, by 3 yrUD[11]	258	128	1.62 P = 0.23	8.9%	Nul P = 1.00	1.74 P = 0.31	1.79 P = 0.23	2.25 P = 0.35	3.6%	260:130UD eOR= 1.69	248:124 eOR= 2.28	Approximately 80% (low pressure)	NA	NA
ABSORB China, by 3 yrUD[11,37]	234	229	1.17 P = 0.71	5.5%	0.33 P = 0.31	2.97 P = 0.16	1.64 P = 0.33	Nul P = 0.16	0.9%	231:231UD eOR= 1.19	NA	16.9%	13.5%	18.1%
EVERBIO II, by 9 moUD[28]	78	160	1.33 P = 0.60	12%	Nul P = 0.33	NA	1.11 P = 0.83	Nul P = 0.33	1%	83:170UD eOR= 1.26	NA	34%	34%	NA
AIDA, by 2 yrUD[29]	924	921	1.17 P= 0.31	10.3%	0.78 P = 0.43	1.60SP = 0.04	1.33 P = 0.15	3.87SP < 0.001	3.5%	941:941UD eOR= 1.17	898:898 eOR= 4.09	74%	74%	19%
DES trials and BVS registry comparators
RESOLUTE All-Comers, by 1 yrUD[13]	1140	1152	1.01 P = 0.94	8.3%2	1.75 P = 0.08	0.98 P = 0.92	0.87 P = 0.50	2.29 P = NS	1.6%	1132:1132 eOR= 1.00	1152:1152UD eOR= 2.26	NA	NA	NA
RESOLUTE All-Comers, by 5 yr UD[13]	1140	1152	1.05 P = 0.61	17.0%	1.14 P = 0.48	1 P = 1.00	1.09 P = 1.58	1.41 P = 0.24	2.4%	2632:2632UD eOR= 0.43	1133:1133 eOR= 2.03	NA	NA	NA
SCAAR Registry, by 2 yrUD[11]	810	67099	NA	NA	NA	NA	NA	2.5 P = 0.006	1.5%2	NA	826:68308UD eOR= 2.47	NA	NA	Nul
Recent meta-analyses of BVS
Polimeni et al[6], at 2 yr3UD	3079	2140	1.33SP = 0.01	9.4%	0.94 P = 0.80	1.66SP < 0.01	1.32 P = 0.05	3.22SP < 0.0001	2.3%	2708:1881 eOR= NA	3214:2234UD eOR= NA	> 61%	61%	NA
Collet et al[7], at 2 yr3UD	996	696	1.48 P = 0.09	8.2%	0.69 P = 0.35	2.25 P = 0.09	1.89SP = 0.02	2.93SP = 0.01	2.2%	616:437 eOR= NA	2759:1930UD eOR= NA	NA	NA	NA
Ha et al[8], mostly at 2 yr3	1379	1095	1.31 P = 0.12	7.7%	0.58 P = 0.23	2.59SP = 0.02	1.70SP = 0.04	2.35SP = 0.02	2.6%	1233:987 eOR= NA	1374:1082 eOR= NA	> 36%	36%	NA
Mahmoud et al [5], at 2 yrUD	3166	2226	1.32SP < 0.01	10.90%	0.75 P = 0.21	1.65 SP < 0.001	1.39 SP = 0.01	3.22SP < 0.0001	2.40%	3206:2258UD eOR= 1.4	3174:2235UD eOR= 3.58	> 34%	34%	NA
Sorrentino et al[9], mostly at 2 yr	3261	2322	1.32 SP < 0.01	9.60%	0.89 P = 0.63	1.62 SP < 0.001	1.40 SP = 0.007	3.15SP < 0.0001	2.40%	3118:2227 eOR= 1.38	3241:2315 eOR= 3.49	> 34%	34%	NA
Ali et al[35], at 2 yr5	3261	2322	1.29 SP < 0.01	9.40%	0.9 P = 0.90	1.64 SP < 0.001	1.39 SP = 0.009	2.99 SP < 0.0001	2.30%	3054:2183 eOR= 1.32	3207:2296 eOR= 3.32	67%	56%	< 51.8%
Zhang et al[36], at > 1 yr3UD	3237	2303	1.37 SP < 0.01	9.96% (7.3%)4	0.92 P = 0.711	1.63 SP < 0.001	1.31 SP = 0.027	3.40 SP < 0.001	2.5% (1.8%)4	2968:2116 eOR= NA	3470:2469UD eOR= NA	NA	NA	NA
Ali et al[39], at 3 yr5UD	2096	1189	1.37 SP = 0.01	11.70%	0.9 P = 0.77	1.68 SP = 0.001	1.41 SP = 0.03	2.83 SP = 0.01	2.40%	2083:1177UD eOR= 1.5	2068:1162 eOR= 4.1	NA	NA	NA
Kang et al [45], at > 2 yr3UD	3179	2239	1.39 SP < 0.001	12.50%	0.86 P = 0.49	1.67 SP < 0.001	1.46 SP = 0.004	3.59 SP < 0.001	2.60%	2957:2083 eOR= NA	3297:2322UD eOR= NA	NA	NA	NA

¹Enrollment is not completed yet (2546/3000 subjects in ABSORB IV trial were allocated in March 2017; presented data are preliminary);

²Primary end-point;

³Odds ratio (OR) was provided by the author instead of RR (estimated OR was calculated from the data provided by the author in the article if applicable);

⁴Pooled incidence of definite or probable stent thrombosis at longest follow-up in patients receiving BVS[36]; ⁵D + L, DerSimonian and Laird random-effect model. The OR, confidence level and relevant sample size were determined with a validated online calculator of Select Statistical Services (https://select-statistics.co.uk/calculators/confidence-interval-calculator-odds-ratio/; https://select-statistics.co.uk/calculators/sample-size-calculator-odds-ratio/; Exeter, United Kingdom) with a 95%CI, estimated relative precision (calculated as a percentage by which the lower limit for the confidence interval is less than the estimated odds ratio) and the known prevalence of the variables. The estimated odds ratio (eOR), which was calculated from the data that were provided by the author in the original article, represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure. Either P value or OR presented inside the cells below the numbers. Cells with “S” depict data with a statistically significant P value (P < 0.05, addressing the question of whether the intervention effect is precisely nil). Cells with “UD” indicate variables with underpowered design by sample size (when the estimated post hoc sample size is bigger than ad hoc one). If not mentioned, the data from meta-analyses presented are from the Fixed effects model.

Table 2 Serial imaging analysis of the artery remodeling in ABSORB cohort A and B trials

Variable	Post-procedure (baseline)	6 mo	12 mo	24 mo	36 mo	60 mo	FriedmanP value
Intravascular ultrasound, 60-mo results of ABSORB cohort B (B1, n = 21, and B2, n = 30) trial
Mean vessel area in mm2, mean ± SD (n), BL-to-FUP P value	14.56 ± 3.82 (21)	14.92 ± 3.78 (21), 0.3925		15.88 ± 4.02 (21), 0.0014S		15.28 ± 4.53 (21), 2.1371	0.0193S
	13.61 ± 2.40 (30)		14.15 ± 2.61 (30), 0.2140		14.25 ± 2.57 (30), 0.0788	13.23 ± 2.70 (28), 0.2701	0.0337S
Mean lumen area in mm2, mean ± SD (n), BL-to-FUP P value	6.75 ± 1.19 (21)	6.59 ± 1.20 (21), 0.0610		7.24 ± 1.91 (21), 0.1995		7.46 ± 2.45 (21), 0.0851	0.0626
	6.31 ± 0.86 (30)		6.31 ± 1.01 (30), 0.5131		6.70 ± 1.48 (30), 0.0858	6.48 ± 1.50 (30), 0.5666	0.2221
Plaque burden in %, mean ± estimated SD (n)1, BL-to-FUP P value	53.64 ± 14.08 (21)	55.83 ± 14.15 (21), < 0.392		54.41 ± 14.35 (21), < 0.202		51.18 ± 16.81 (21), < 2.142	< 0.062
	53.64 ± 9.46 (30)		55.41 ± 10.22 (30), < 0.512		52.98 ± 11.70 (30), < 0.092	51.02 ± 11.81 (30), < 0.562	< 0.222
Mean plaque area in mm2, mean ± SD (n), BL-to-FUP P value	7.81 ± 2.98 (21)	8.33 ± 2.88 (21), 0.0660		8.64 ± 2.85 (21), 0.0004S		7.75 ± 2.62 (21), 4.4007	0.0025S
	7.30 ± 1.85 (30)		7.84 ± 1.92 (30), 0.0220S		7.55 ± 1.58 (30), 0.8121	6.79 ± 1.90 (28), 0.0108S	< 0.0001S
Intravascular ultrasound, 36-mo results of ABSORB cohort B (B1, n = 33, and B2, n = 45) trial
Mean vessel area in mm2, mean ± SD (n), BL-to-FUP P value	14.04 ± 3.80 (33)	14.44 ± 3.82 (33), 0.008S		15.35 ± 4.05 (33), < 0.001S		NA	NA
	13.79 ± 2.37 (45)		14.43 ± 2.64 (45), 0.03S		14.58 ± 2.67 (45), 0.002S	NA	0.18
Mean lumen area in mm2, mean ± SD (n), BL-to-FUP P value	6.53 ± 1.24 (33)	6.36 ± 1.18 (33), 0.02S		6.85 ± 1.78 (33),0.35		NA	NA
	6.29 ± 0.90 (45)		6.35 ± 1.17 (45), NS		6.81 ± 1.62 (45), 0.05S	NA	0.007S
Plaque burden in %, mean ± estimated SD (n)1, BL-to-FUP P value	53.49 ± 14.48 (33)	55.96 ± 14.80 (33), < 0.02S		55.37 ± 14.61 (33), < 0.35		NA	NA
	54.39 ± 9.35 (45)		55.99 ± 10.32 (45), NS		53.29 ± 12.68 (45), < 0.05S	NA	NA
Mean plaque area in mm2, mean ± SD (n), BL-to-FUP P value	7.52 ± 2.84 (33)	8.08 ± 2.87 (33), < 0.001S		8.49 ± 2.89 (33), < 0.001S		NA	NA
	7.50 ± 1.82 (45)		8.08 ± 1.94 (45), < 0.001S		7.77 ± 1.73 (45), NS	NA	0.004
Intravascular ultrasound, 24-mo (n = 25), and MSCT, 60 mo (n = 18), results of ABSORB cohort A trial
Mean vessel area in mm2, mean ± SD (n), BL-to-FUP P value	13.49 ± 3.74 (25)	13.79 ± 3.84 (25), 0.98	NA	12.75 ± 3.43 (19), 0.68	NA	NA	NA
	NA	NA	NA	13.17 (18) (18 mo baseline)	NA	11.93 (18), 0.26	NA
Mean lumen area in mm2, mean ± SD (n), BL-to-FUP P value	6.04 ± 1.12 (25)	5.19 ± 1.33 (25), < 0.0001S	NA	5.47 ± 2.11 (19), 0.12	NA	NA	NA
	NA	NA	NA	4.47 (18) (18 mo baseline)	NA	4.29 (18), 0.11	NA
Plaque burden in %, mean ± estimated SD (n)1, BL-to-FUP P value	55.23 ± 15.31 (25)	62.36 ± 17.37 (25), < 0.98	NA	57.10 ± 22.02 (19), < 0.68	NA	NA	NA
	NA	NA	NA	66.06 (18) (18 mo baseline)	NA	64.04 (18), < 0.26	NA
Mean plaque area in mm2, mean ± SD (n), BL-to-FUP P value	7.44 ± 2.83 (25)	8.60 ± 2.85 (25), < 0.0001S	NA	7.10 ± 2.02 (19), 0.80	NA	NA	NA
	NA	NA	NA	8.23 (18) (18 mo baseline)	NA	7.10 (18), 0.23	NA

Numbers are expressed in mean ± SD or n.

¹The SD cannot be directly calculated due to unavailability of the patient-by-patient matrix of the ABSORB trial, and presented as either a 5% deviation or adjusted by the maximum deviation for both numerator and denominator;

²The P value cannot be directly calculated due to unavailability of the patient-by-patient matrix of ABSORB trial, and performed as an estimated P value adjusted by the maximum P value in either numerator or denominator. The cells with “S” performed statistically significant changes (P < 0.05) of the variables. NS: Non-significant (P value > 0.05); NA: Non-available or not applicable.