Impact of switching from cigarette smoking to tobacco heating system use on biomarkers of potential harm in a randomized trial

Figures & data

Table 1. Biomarkers of potential harm^a. (the eight core BoPH are highlighted.).

Pathomechanism	Indicative BoPH	Matrix	Reported impact of smoking cessation
Lipid metabolism	High-density lipoprotein cholesterol (HDL-C)	Serum	Increase <1 year^1,23
	Apolipoprotein A1 (Apo A1)	Serum	Increase <1 year^24
	Low-density lipoprotein cholesterol (LDL-C)	Serum	Decrease after at least 2 years^25
	Apolipoprotein B (Apo B)	Serum	Decrease after at least 2 years^31
Endothelial dysfunction & platelet activation	Soluble intercellular adhesion molecule-1 (sICAM-1)	Serum	<1 year^2,3,4,2,21
	11-dehydrothromboxane B2 (11-DTX-B2)	Serum	<1 year^11,12,13
	Fibrinogen	Plasma	Decrease after at least 2 years^28
	Platelet count	Blood	Not clear, highly variable in the literature^29,30
	Albumin^23	Urine	Not expected to change within 1 year
Lung function	Forced expiratory volume in 1 s BD (FEV1)	–	<1 year^16,17,18,19
	Forced vital capacity (FVC) %pred post BD	–	Not expected to change within 1 year
	Forced expiratory flow (FEF)25-75% post BD	–	Not expected to change within 1 year
	Forced expiratory volume in one second/ Forced vital capacity (FEV1/FVC) post BD ratio	–	Not expected to change within 1 year
Inflammation & oxidative stress	White blood cell (WBC) count (total count)	Blood	<1 year^5,6,7,8
	8-Epi-prostaglandin F2α (8-epi-PGF2α)	Urine	<1 year^14,15
	Myeloperoxidase (MPO)	Serum	Decrease after at least 2 years^27
	High-sensitivity C-reactive protein (hs-CRP)	Serum	Decrease after at least 2–5 years^21
Oxygen transport	Carboxyhemoglobin (COHb)	Serum	<1 year^9,10
Carcinogenicity	Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (total NNAL)	Urine	<1 year^20

BD: bronchodilator.

^aThese BoPH represent some of the main pathomechanisms underlying CVD, COPD, and cancer, as described by the U.S. Surgeon General’s report on smoking cessation (U.S. Department of Health and Human Services 2020).

1 (Forey et al. 2013), 2 (Palmer et al. 2002), 3 (Tsai et al. 2012), 4 (Scott et al. 2000), 5 (Hammett et al. 2007), 6 (Haustein et al. 2002), 7 (Jensen et al. 1998), 8 (Lee et al. 2014), 9 (Ergüder et al. 2006), 10 (Kambam et al. 1986), 11 (Rångemark et al. 1993), 12 (Roethig et al. 2007), 13 (Saareks et al. 2001), 14 (Chehne et al. 2002), 15 (Pilz et al. 2000), 16 (Bake et al. 1977), 17 (Lee and Fry 2010), 18 (Buist et al. 1976), 19 (Willemse et al. 2005), 20 (Carmella et al. 2009), 21 (El-Deek et al. 2013), 22 (Voulgari et al. 2011), 23 (Gordon et al. 1989), 24 (Stubbe et al. 1982), 25 (Brischetto et al. 1983), 26 (Tonstad and Urdal 2002), 27 (Andelid et al. 2007), 28 (Sinha et al. 2005), 29 (Caponnetto et al. 2011), 30 (Morita et al. 2005), 31 (Tan et al. 2008).

Figure 1. Flow of participants through the ‘exposure response study’ and study extension. GCP: good clinical practice; THS: tobacco Heating System.

Table 2. Summary of demographic data and smoking-related characteristics at baseline; full analysis by product use group.

Variables	Statistics	THS use (n = 230)	Dual use (n = 152)	Cig use (n = 424)	Other use (n = 51)
Sex
Male	n (%)	143 (62.2)	85 (55.9)	244 (57.5)	32 (62.7)
Female	n (%)	87 (37.8)	67 (44.1)	180 (42.5)	19 (37.3)
Age (years)	n (%)	230 (100)	152 (100)	424 (100)	51 (100)
	Mean (SD)	43.8 (9.68)	44.2 (9.76)	45.2 (9.54)	44.5 (8.21)
Race
White	n (%)	182 (79.1)	123 (80.9)	338 (79.7)	36 (70.6)
Black	n (%)	41 (17.8)	25 (16.4)	73 (17.2)	12 (23.5)
Others^a	n (%)	7 (3.0)	2 (1.3)	13 (3.0)	3 (5.8)
Height (cm)	n (%)	230 (100)	152 (100)	424 (100)	51 (100)
	Mean (SD)	173 (10.3)	172 (8.97)	173 (9.57)	172 (10.2)
Weight (kg)	n (%)	230 (100)	152 (100)	424 (100)	51 (100)
	Mean (SD)	81.4 (17.0)	80.0 (15.3)	81.2 (15.6)	79.1 (18.1)
BMI (kg/m^2)	n (%)	230 (100)	152 (100)	424 (100)	51 (100)
	Mean (SD)	27.0 (4.06)	26.9 (4.25)	27.1 (4.13)	26.6 (4.91)
Underweight	n (%)	1 (0.4)	0	0	0
Normal weight	n (%)	77 (33.5)	55 (36.2)	142 (33.5)	17 (33.3)
Overweight	n (%)	88 (38.3)	57 (37.5)	163 (38.4)	19 (37.3)
Obese	n (%)	64 (27.8)	40 (26.3)	119 (28.1)	15 (29.4)
Waist circumference (cm)	n (%)	230 (100)	152 (100)	422 (99.5)	50 (98.0)
	Mean (SD)	94.6 (16.6)	96.2 (15.3)	94.5 (14.8)	93.3 (12.0)
COPD stage
Normal	n (%)	213 (92.6)	139 (91.4)	396 (93.4)	47 (92.2)
GOLD1: Mild	n (%)	14 (6.1)	9 (5.9)	24 (5.7)	4 (7.8)
GOLD2: Moderate	n (%)	3 (1.3)	4 (2.6)	4 (0.9)	0
Others	n (%)	0	0	0	0
Smoking duration	Mean (SD)	25.6 (9.48)	25.6 (10.0)	26.7 (10.1)	25.7 (10.2)
Smoking intensity^b	Mean (SD)	18.4 (6.88)	19.5 (7.82)	19.5 (7.87)	20.5 (11.0)
Pack year smoking history	Mean (SD)	22.7 (12.3)	23.3 (14.1)	25.0 (15.9)	23.4 (14.6)

^aOthers include American Indian or Alaska Native, Asian, and Native Hawaiian, or other Pacific Islander.

^bAverage daily cigarette consumption over the last year.

BMI: body mass index; cm: centimeters; COPD: chronic obstructive pulmonary disease; GOLD: Global Initiative for Chronic Obstructive Lung Disease; kg: kilograms; Other use: General category encompassing participants with missing product use, or participants using e-cigarettes or other tobacco products, participants who quit, or participants who switched across different use patterns between consecutive analysis periods; SD: standard deviation.

Figure 2. Mean relative differences or reductions (and 95% confidence intervals) between the predTHS and cig groups after 3, 6, and 12 months of product use. A, lipid metabolism; B, endothelial and platelet function; C, lung function; D, inflammation and oxidative stress; E, oxygen transport; and F, carcinogenicity.

Table 3. Levels of BoPHs across the study groups and inferential analyses between the predTHS and dual groups and the cigarette (cig) group at 3, 6, and 12 months.

Patho­­mechanisms	BoPH	Product group	Baseline	Month 3	Month 6	Month 12	Relative difference/relative change Month 3	Relative difference/ relative change Month 6	Relative difference/relative change Month 12
Lipid metabolism	HDL-C (mg/dL)^a mean (95% CI) change from baseline	PredTHS	53.5 (51.6; 55.5)	54.0 (51.6; 56.4) 0.5 (−0.9; 1.8)	54.1 (51.4; 56.7) 0.7 (−0.9; 2.4)	52.2 (49.5; 54.8) −0.4 (−2.0; 1.2)	1.6 (0.0; 3.2)	3.1 (1.3; 4.9)	1.8 (−0.2; 3.7)
		Dual use	55.1 (52.3; 58.0)	56.2 (52.8; 59.6) 0.7 (−1.4; 2.9)	56.3 (52.7; 59.9) 1.2 (−1.0; 3.3)	54.0 (49.7; 58.4) 0.7 (−1.9; 3.2)	1.9 (−0.1; 3.8)	3.4 (1.2; 5.6)	2.8 (0.6; 5.0)
		Cig	53.7 (52.1; 55.3)	52.5 (51.0; 54.1) −1.1 (−2.0; −0.1)	50.9 (49.4; 52.4) −2.5 (−3.6; −1.5)	50.6 (48.9; 52.3) −2.2 (−3.4; −1.0)	ref	ref	ref
	Apo A1 (mg/dL) mean (95% CI) change from baseline	PredTHS	145 (141; 148)	145 (141; 149) 0.4 (−2.1; 2.9)	146 (141; 150) 1.3 (−1.7; 4.3)	143 (139; 148) −0.3 (−3.7; 3.2)	0.5 (−2.5, 3.5)	3.7 (0.3; 7.0)	2.1 (−1.8; 6.0)
		Dual use	147 (142; 152)	149 (144; 154) 1.7 (−1.5; 4.9)	148 (143; 153) 1.3 (−1.8; 4.5)	144 (137; 151) −0.3 (−4.7; 4.0)	2.6 (−1.1; 6.2)	4.6 (0.5; 8.6)	2.4 (−2.2; 6.9)
		Cig	146 (143; 149)	146 (143; 149) −0.2 (−2.3; 1.9)	143 (140; 146) −3.2 (−5.3; −1.0)	142 (139; 146) −3.1 (−5.6; −0.6)	ref	ref	ref
	Apo B (mg/dL) mean (95% CI) change from baseline	PredTHS	94.3 (91.1; 97.4)	92.0 (88.8; 95.2) −2.4 (−4.5; −0.4)	92.6 (89.2; 96.0) −1.7 (−3.9; 0.5)	92.9 (88.9; 97.0) −1.6 (−3.8; 0.6)	−2.1 (−4.5; 0.3)	−1.5 (−4.2; 1.1)	0.1 (−2.7; 2.9)
		Dual use	92.3 (87.6; 97.0)	91.7 (87.1; 96.3) −0.4 (−3.0; 2.1)	91.0 (86.3; 95.8) −1.0 (−3.8; 1.7)	89.6 (84.3; 94.9) −1.6 (−4.6; 1.6)	−0.7 (−3.6; 2.2)	−1.2 (−4.4; 2.1)	−1.5 (−4.8; 1.8)
		Cig	97.6 (95.2; 100)	97.0 (94.5; 99.4) −0.7 (−2.3; 0.8)	97.4 (94.8; 100.0) −0.9 (−2.7; 0.8)	95.2 (92.5; 98.0) −2.8 (−4.8; −0.8)	ref	ref	ref
	LDL-C (mg/dL) mean (95% CI) change from baseline	PredTHS	125 (121; 129)	123 (118; 127) −2.5 (−5.4; 0.5)	124 (119; 128) −1.8 (−5.1; 1.4)	124 (118; 130) −0.5 (−3.8; 2.8)	−2.1 (−5.6; 1.4)	−1.7 (−5.4; 2.1)	1.2 (−3.2; 5.5)
		Dual use	123 (117; 129)	121 (115; 128) −2.1 (−5.9; 1.7)	122 (115; 129) −0.9 (−4.8; 3.1)	121 (113; 129) −1.4 (−6.4; 3.7)	−2.3 (−6.4; 1.9)	−1.0 (−5.6; 3.5)	−0.9 (−6.0; 4.2)
		Cig	129 (125; 133)	128 (125; 131) −1.1 (−3.4; 1.2)	128 (125; 132) −1.1 (−3.6; 1.5)	127 (122; 131) −2.7 (−5.7; 0.3)	ref	ref	ref
Endothelial dysfunction & platelet activation	sICAM−1 (ng/mL) mean (95% CI) % change from baseline	predTHS	259 (247; 272)	254 (242; 267) −0.6 % (−2.9; 1.6)	252 (239; 266) −1.1% (−3.8; 1.7)	246 (230; 263) −2.9% (−6.2; 0.4)	−1.9% (−4.7; 1.1)	−3.2% (−6.1; −0.3)	−3.1% (−6.1; 0.0)
		Dual use	270 (254; 287)	271 (256; 288) 2.2% (−0.9; 5.3)	270 (253; 288) −0.1% (−3.1; 2.8)	269 (252; 286) −2.7% (−6.3; 0.9)	1.2 % (−2.3; 4.9)	−1.5 % (−4.9; 2.2)	−1.6 % (−5.2; 2.0)
		Cig	264 (252; 277)	263 (251; 276) 1.7% (−0.5; 4.0)	266 (253; 279) 2.3% (−0.6; 5.2)	258 (244; 272) −1.5% (−3.1; 0.2)	ref	ref	ref
	11-DTX-B2 (pg/mg creat.) mean (95% CI) % change from baseline	predTHS	585 (532; 644)	498 (449; 551) 8.6% (−3.3; 20.5)	492 (443; 547) 7;0% (−5.3; 19.2)	582 (518; 654) 26.0% (7.3; 44.8)	−3.3% (−12.5; 6.9)	−4.5% (−14.3; 6.5)	−3.4% (−14.3; 8.7)
		Dual use	586 (513; 669)	579 (510; 659) 28.5% (6.1; 50.8)	533 (465; 612) 25.6% (−6.5; 57.8)	595 (510; 693) 48.3% (7.2; 89.3)	9.6 % (−2.8; 23.6)	−0.6% (−12.8; 13.4)	2.6 % (−10.8; 18.0)
		Cig	575 (534; 620)	520 (482; 561) 16.0 % (6.2; 25.7)	518 (478; 561) 25.4 % (10.4; 40.5)	586 (538; 638) 32.3% (17.0; 47.6)	ref	ref	ref
	Platelet count (GI/L) mean (95% CI) % change from baseline	predTHS	239 (231; 246)	241 (234; 249) 1.9 % (0.0; 3.9)	250 (241; 258) 5.6% (3.4; 7.9)	248 (239; 258) 4.5% (1.9; 7.0)	−1.2% (−3.6; 1)	2% (−0.5; 5)	0% (−2.4; 3)
		Dual use	236 (227; 245)	239 (230; 249) 2.7 % (0.0; 5.4)	242 (233; 252) 3.5% (0.8; 6.3)	231 (221; 242) 0.6% (−2.7; 3.9)	−0.8% (−3.8; 2)	0% (−2.7; 3)	−3.8% (- 6.8; −0.7)
		Cig	241 (236; 247)	246 (240; 252) 3.4% (1.6; 5.2)	246 (240; 253) 3.5% (1.7; 5.3)	248 (242; 255) 3.6% (1.7; 5.4)	ref	ref	ref
	Fibrinogen (mg/dL) Mean (95% CI) % change from baseline	predTHS	327 (318; 336)	323 (315; 332) 0.9% (−2.0; 3.8)	321 (312; 331) 1.1% (−2.4; 4.7)	323 (311; 335) 2.2 % (−1.7; 6.2)	−0.9% (−4.1; 2)	−2.4% (−5.2; 1)	−0.8 % (−4.1; 3)
		Dual use	337 (324; 352)	332 (319; 344) 1.1% (−2.6; 4.8)	328 (316; 340) −1.1 % (−4.8; 2.6)	337 (324; 350) 1.7% (−2.1; 5.5)	−0.1% (−4; 4)	−2.5% (−6; 1)	1% (−2.6; 6)
		Cig	338 (331; 346)	333 (324; 343) 1.4% (−0.8; 3.6)	338 (331; 345) 1.9 % (−0.3; 4.1)	337 (328; 345) 1.6% (−1.0; 4.2)	ref	ref	ref
Lung function	FEV1%pred post-bronchodilator^b change from baseline	predTHS	96.4 (94.8; 98.1)	96.1 (94.4; 97.9) −0.4 (−1.1; 0.3)	95.4 (93.7; 97.1) −1.3 (−2.2; −0.5)	93.2 (91.1; 95.2) −2.8 (−3.9; −1.7)	0.8 (0.0; 1.6)	1.3 (0.3; 2.3)	0.9 (−0.3; 2.2)
		Dual use	95.1 (92.7; 97.4)	94.8 (92.5; 97.1) −0.4 (−1.2; 0.3)	93.8 (91.4; 96.1) −1.0 (−2.1; 0.1)	91.1 (88.2; 94.1) −1.8 (−3.0; −0.6)	0.6 (−0.4; 1.6)	1.4 (0.2; 2.7)	1.3 (−0.2; 2.7)
		Cig	95.9 (94.6; 97.1)	94.6 (93.3; 95.9) −1.2 (−1.7; −0.7)	93.4 (92.0; 94.8) −2.6 (−3.3; −2.0)	92.3 (90.7; 94.0) −3.7 (−4.4; −2.9)	ref	ref	ref
	FVC %pred Post-bronchodilator change from baseline	predTHS	97.2 (95.5; 98.8)	97.3 (95.6; 98.9) −0.1 (−0.7; 0.5)	97.1 (95.4; 98.9) −0.6 (−1.3; 0.0)	95.0 (92.9; 97.1) −1.9 (−2.8; −1.1)	0.6 (−0.1; 1.3)	0.7 (−0.1; 1.5)	0.5 (−0.4; 1.5)
		Dual use	95.7 (93.5; 97.9)	95.7 (93.5; 98.0) −0.1 (−0.9; 0.7)	95.6 (93.3; 97.8) 0.1 (−0.9; 1.0)	92.6 (89.8; 95.4) −0.7 (−1.8; 0.4)	0.6 (−0.3; 1.4)	1.1 (0.2; 2.1)	1.4 (0.3; 2.6)
		Cig	96.4 (95.2; 97.7)	95.7 (94.4; 97.0) −0.7 (−1.1; −0.3)	95.5 (94.2; 96.8) −1.3 (−1.8; −0.8)	94.2 (92.6; 95.7) −2.3 (−2.9; −1.7)	ref	ref	ref
	FEF25-75%pred Post-bronchodilator change from baseline	Pred THS	103 (99.4; 107)	103 (98.9; 106) −0.2 (−2.1; 1.6)	99.5 (95.8; 103) −3.5 (−5.6; −1.4)	98.3 (93.7; 103) −4.3 (−6.9; −1.9)	1.7 (−0.6; 4.0)	1.9 (−0.8; 4.6)	2.2 (−0.7; 5.1)
		Dual use	102 (97.3; 108)	102 (96.9; 107) −0.9 (−3.4; 1.5)	98.5 (93.4; 104) −3.2 (−6.0; −0.4)	97.5 (90.8; 104) −3.8 (−6.5; −1.1)	0.8 (−2.0; 3.5)	1.8 (−1.4; 5.0)	1.9 (−1.5; 5.3)
		Cig	103 (99.9; 105)	101 (98.0; 103) −2.0 (−3.4; −0.5)	96.9 (94.0; 99.8) −5.3 (−7.0; −3.6)	96.1 (92.8; 99.4) −6.7 (−8.6; −4.7)	ref	ref	ref
	FEV1/FVC ratio % Post-bronchodilator change from baseline	THS	78.9% (78.1; 79.7)	78.6% (77.8; 79.5) −0.2 (−0.6; 0.2)	78.1 % (77.2; 78.9) −0.5 (−0.9; −0.1)	78.1 % (77.1; 79.2) −0.7 (−1.2; −0.2)	0.2 (−0.3; 0.7)	0.6 (0.0; 1.2)	0.5 (−0.2; 1.2)
		Dual use	79.0% (78.0; 80.0)	78.8% (77.7; 79.9) −0.2 (−0.9; 0.4)	78.0% (76.9; 79.2) −0.9 (−1.6; −0.2)	78.2% (76.9; 79.6) −0.9 (−1.6; −0.2)	0.1 (−0.5; 0.8)	0.3 (−0.5; 1.0)	0.1 (−0.7; 0.9)
		Cig	78.8% (78.3; 79.4)	78.5 % (77.9; 79.0) −0.5 (−0.8; −0.1)	77.5% (76.9; 78.2) −1.2 (−1.6; −0.8)	77.6 % (76.9; 78.4) −1.2 (−1.69; −0.7)	ref	ref	ref
Inflammation/oxidative stress	WBC count (GI/L) mean (95% CI) change from baseline	predTHS	7.33 (7.09; 7.58)	6.95 (6.73; 7.17) −0.39 (−0.59; −0.18)	6.98 (6.70; 7.25) −0.38 (−0.62; −0.15)	6.73 (6.47; 6.99) −0.52 (−0.75; −0.29)	−0.47 (−0.73; −0.22)	−0.43 (−0.70; −0.16)	−0.41 (−0.69; −0.13)
		Dual use	7.47 (7.13; 7.80)	7.41 (7.01; 7.81) −0.06 (−0.34; 0.23)	7.41 (7.00; 7.82) 0.01 (−0.33; 0.36)	7.28 (6.85; 7.71) −0.15 (−0.45; 0.15)	−0.13 (−0.43; 0.17)	−0.04 (−0.36; 0.29)	0.03 (−0.30; 0.36)
		Cig	7.47 (7.28; 7.67)	7.53 (7.32; 7.74) 0.07 (−0.11; 0.24)	7.48 (7.28; 7.69) 0.03 (−0.14; 0.20)	7.31 (7.07; 7.54) −0.18 (−0.39; 0.03)	ref	ref	ref
	8-Epi-PGF2α (pg/mg creat.) mean (95% CI) % change from baseline	predTHS	355 (333; 379)	324 (303; 347) 0.9% (−6.2; 7.9)	317 (297; 340) −1.9% (−8.5; 4.8)	307 (279; 338) −3.1% (−10.7; 4.4)	−5.9% (−11.5; 0.0)	−7.5% (−13.2; −1.5)	−7.2% (−14.7; 1.0)
		Dual use	380 (352; 410)	378 (348; 411) 9.7% (1.0; 18.3)	345 (317; 376) −2.3% (−9.6; 5.1)	326 (293; 362) −5.8% (−13.5; 1.9)	4.0 % (−3.4; 12.0)	−4.8% (−11.8; 2.8)	−5.0% (−14.0; 5.0)
		Cig	360 (344; 377)	351 (334; 369) 5.7% (0.6; 10.9)	348 (331; 365) 7.8% (−2.5; 18.2)	327 (307; 348) −2.0% (−6.2; 2.2)	ref	ref	ref
	MPO (μg/L) mean (95% CI) % change from baseline	predTHS	126 (115; 138)	129 (117; 142) 35.3% (21.7; 48.9)	137 (123; 152) 38.0% (25.0; 50.9)	191 (175; 209) 90.0% (69.7; 110)	−12.8% (−21.5; −3.3)	−20.3% (−28.3; −11.4)	−12.8 % (−20.6; −4.2)
		Dual use	130 (114; 149)	174 (151; 201) 69.2% (46.3; 92.1)	180 (157; 207) 79.1% (52.3; 106)	235 (205; 270) 143% (79.5; 207)	15% (1; 30)	3% (−9.5; 17)	3% (−8; 15)
		Cig	124 (116; 133)	145 (135; 156) 63.6% (39.7; 87.5)	168 (156; 181) 91.3% (62.0; 121)	217 (204; 232) 129% (105; 154)	ref	ref	ref
	High-sensitivity C-reactive protein (mg/L) mean (95% CI) % change from baseline	predTHS	1.59 (1.37; 1.85)	1.54 (1.33; 1.79) 46.6% (23.2; 69.9)	1.59 (1.34; 1.88) 94.9% (42.4; 147)	1.57 (1.29; 1.90) 101% (−2.46; 204)	−7.8% (−19.7; 6)	−12.3% (−24.5; 2)	−10% (−23; 5)
		Dual use	1.58 (1.29; 1.93)	1.89 (1.51; 2.36) 178% (61.1; 295)	1.80 (1.45; 2.22) 82.0% (35.4; 129)	2.46 (1.97; 3.08) 131% (39.0; 224)	14% (−3.3; 35)	−2.6% (−18.7; 17)	25% (4; 50)
		Cig	1.81 (1.61; 2.03)	1.84 (1.63; 2.07) 52.6% (33.0; 72.3)	1.98 (1.76; 2.22) 119% (61.0; 176)	1.94 (1.70; 2.21) 66.3% (34.6; 97.9)	ref	ref	ref
Carcino­genicity	Total NNAL (pg/mg creat.) mean (95% CI) % change from baseline	THS	295 (263; 331)	158 (135; 186) −17.0% (−31.1; −2.9)	143 (118; 174) −16.5% (−36.2; 3.2)	133 (105; 168) −25.6 % (−35.2; −16.0)	−42.1% (−48.5; −34.9)	- 42.9% (−50.4; −34.2)	−46.3% (−54.8; −36.2)
		Dual use	342 (298; 391)	287 (248; 332) −0.6% (−11.9; 10.8)	288 (246; 337) −3.3% (−12.7; 6.2)	253 (207; 309) −5.6 % (−17.0; 5.7)	−7.87 % (−19.9; 6.0)	−5.24 % (−20.0; 12.3)	−11.7% (−27.6; 7.8)
		Cig	314 (288; 343)	293 (268; 321) 42.5% (−23.5; 109)	279 (251; 311) 9.1% (−2.4; 20.7)	269 (238; 305) 30.0 % (−10.5; 70.5)	ref	ref	ref
Oxygen Transport	COHb (%) mean (95% CI) % change from baseline	THS	4.30 (4.03; 4.58)	2.80 (2.53; 3.10) −19.6% (−26.4; −12.8)	2.84 (2.51; 3.20) −15.2 % (−23.0; −7.4)	2.59 (2.24; 3.01) −24.3% (−32.8; −15.8)	−31.2% (−37.0; −24.8)	−32.0% (−38.3; −25.1)	−31.7% (−39.1; −23.3)
		Dual use	4.53 (4.23; 4.86)	4.14 (3.76; 4.57) 0.5% (−7.5; 8.5)	4.23 (3.80; 4.70) 6.0% (−1.6; 13.7)	3.92 (3.44; 4.46) −5.0 % (−14.1; 4.1)	−4.2 % (−14.0; 6.6)	−0.8% (−11.7; 11.5)	−5.9% (−17.9; 7.9)
		Cig	4.55 (4.34; 4.76)	4.26 (4.02; 4.51) 4.0% (−0.9; 8.9)	4.38 (4.16; 4.61) 7.9% (1.6; 14.1)	4.06 (3.77; 4.38) 3.1% (−3.0; 9.2)	ref	ref	ref

Apo A1 : apolipoprotein A1; Apo B: apolipoprotein B; BD: bronchodilator; %chg-bas: % of change from baseline; Cig: cigarette smoker; COHb: carboxyhemoglobin; 11-DTX-B2 : 11-dehydrothromboxane B2; 8-epi-PGF_2α: 8-epi-prostaglandin F_2α; FEF_25-75%pred: forced expiratory flow between 25% and 75% of FVC % predicted; FEV₁/FVC ratio %: forced expiratory volume in 1 s/forced vital capacity ratio %; FEV₁%pred: forced expiratory volume in 1 s %predicted; FVC %pred: forced vital capacity % predicted; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; MPO: myeloperoxidase; NNAL : 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; predTHS: predominant THS user; sICAM-1 : soluble intercellular adhesion molecule-1; WBC: white blood cell.

Note: The difference and ratio calculations were further adjusted on diet for HDL level and %pred FEV₁ for dual use versus cigarette smoking.

Note: Relative change refers to negative reduction. For example, if the ratio of THS vs. Cig is 0.8, then the relative change is -20%.

Note: Adjusted least squares (LS) means and confidence intervals (CI) from a mixed model analysis conducted with original values, with visit, baseline value and its interaction with visit, sex, White origin, age, product use pattern category and its interaction with visit, and smoking intensity as fixed-effect factors and site as a random effect.

^a HDL-C level was also adjusted on diet.

^b %FEV1 was not adjusted on age but was adjusted on diet.

Figure 3. Mean relative difference or reduction (and 95% confidence intervals) between the predTHS and cig groups according to 2CyEMA quartile distribution for the set of eight BoPHs after 3, 6, and 12 months of product use. A, WBC (GI/L); B, FEV1%pred; C, HDL-C; D, sICAM-1; E, 8-epi-PGF2α; F, 11-DTX-B2; G, COHb; and H, total NNAL.

U.S. Department of Health and Human Services. 2020. Smoking cessation: a report of the Surgeon General. Smoking cessation: a report of the Surgeon General. Washington (DC): US Department of Health and Human Services.

 Google Scholar

Forey BA, Fry JS, Lee PN, Thornton AJ, Coombs KJ. 2013. The effect of quitting smoking on HDL-cholesterol - A review based on within-subject changes. Biomark Res. 1(1):26. doi:10.1186/2050-7771-1-26

 PubMedGoogle Scholar

Palmer RM, Stapleton JA, Sutherland G, Coward PY, Wilson RF, Scott DA. 2002. Effect of nicotine replacement and quitting smoking on circulating adhesion molecule profiles (sICAM-1, sCD44v5, sCD44v6). Eur J Clin Invest. 32(11):852–857. doi:10.1046/j.1365-2362.2002.01067.x

 PubMed Web of Science ®Google Scholar

Tsai JS, Guo FR, Chen SC, Lue BH, Lee LT, Huang KC, Chen CY, Hung SH, Chuang LM, Chen CY. 2012. Changes of serum adiponectin and soluble intercellular adhesion molecule-1 concentrations after smoking cessation. Clin Chem Lab Med. 50(6):1063–1069. doi:10.1515/cclm-2011-0852

 PubMed Web of Science ®Google Scholar

Scott DA, Stapleton JA, Wilson RF, Sutherland G, Palmer RM, Coward PY, Gustavsson G. 2000. Dramatic decline in circulating intercellular adhesion molecule-1 concentration on quitting tobacco smoking. Blood Cells Mol Dis. 26(3):255–258. doi:10.1006/bcmd.2000.0304

 PubMed Web of Science ®Google Scholar

Hammett CJ, Prapavessis H, Baldi JC, Ameratunga R, Schoenbeck U, Varo N, French JK, White HD, Stewart RA. 2007. Variation in blood levels of inflammatory markers related and unrelated to smoking cessation in women. Prev Cardiol. 10(2):68–75. doi:10.1111/j.1520-037x.2007.05957.x

 PubMedGoogle Scholar

Haustein KO, Krause J, Haustein H, Rasmussen T, Cort N. 2002. Effects of cigarette smoking or nicotine replacement on cardiovascular risk factors and parameters of haemorheology. J Intern Med. 252(2):130–139. doi:10.1046/j.1365-2796.2002.01014.x

 PubMed Web of Science ®Google Scholar

Jensen EJ, Pedersen B, Frederiksen R, Dahl R. 1998. Prospective study on the effect of smoking and nicotine substitution on leucocyte blood counts and relation between blood leucocytes and lung function. Thorax. 53(9):784–789. doi:10.1136/thx.53.9.784

 PubMed Web of Science ®Google Scholar

Lee PN, Forey BA, Fry JS, Thornton AJ, Coombs KJ. 2014. The effect of quitting smoking on white blood cell count - A review based on within-subject changes. http://www.pnlee.co.uk/documents/refs/lee2014D.pdf

 Google Scholar

Ergüder IB, Ergüder T, Ozkan C, Bozkurt N, Soylu K, Devrim E, Durak I. 2006. Short-term effects of smoking cessation on blood antioxidant parameters and paraoxonase activity in healthy asymptomatic long-term cigarette smokers. Inhal Toxicol. 18(8):575–579. doi:10.1080/08958370600686325

 PubMed Web of Science ®Google Scholar

Kambam JR, Chen LH, Hyman SA. 1986. Effect of short-term smoking halt on carboxyhemoglobin levels and P50 values. Anesth Analg. 65(11):1186–1188.

 PubMed Web of Science ®Google Scholar

Rångemark C, Ciabattoni G, Wennmalm A. 1993. Excretion of thromboxane metabolites in healthy women after cessation of smoking. Arterioscler Thromb. 13(6):777–782. doi:10.1161/01.atv.13.6.777

 PubMedGoogle Scholar

Roethig HJ, Zedler BK, Kinser RD, Feng S, Nelson BL, Liang Q. 2007. Short-term clinical exposure evaluation of a second-generation Electrically Heated Cigarette Smoking System. J Clin Pharmacol. 47(4):518–530. doi:10.1177/0091270006297686

 PubMed Web of Science ®Google Scholar

Saareks V, Ylitalo P, Alanko J, Mucha I, Riutta A. 2001. Effects of smoking cessation and nicotine substitution on systemic eicosanoid production in man. Naunyn Schmiedebergs Arch Pharmacol. 363(5):556–561. doi:10.1007/s002100100398

 PubMed Web of Science ®Google Scholar

Chehne F, Oguogho A, Lupattelli G, Palumbo B, Sinzinger H. 2002. Effect of giving up cigarette smoking and restarting in patients with clinically manifested atherosclerosis. Prostaglandins Leukot Essent Fatty Acids. 67(5):333–339. doi:10.1054/plef.2002.0438

 PubMed Web of Science ®Google Scholar

Pilz H, Oguogho A, Chehne F, Lupattelli G, Palumbo B, Sinzinger H. 2000. Quitting cigarette smoking results in a fast improvement of in vivo oxidation injury (determined via plasma, serum and urinary isoprostane). Thromb Res. 99(3):209–221. doi:10.1016/s0049-3848(00)00249-8

 PubMed Web of Science ®Google Scholar

Bake B, Oxhöj H, Sixt R, Wilhelmsen L. 1977. Ventilatory lung function following two years of tobacco abstinence. Scand J Respir Dis. 58(6):311–318.

 PubMedGoogle Scholar

Lee PN, Fry JS. 2010. Systematic review of the evidence relating FEV1 decline to giving up smoking. BMC Med. 8(1):84. doi:10.1186/1741-7015-8-84

 PubMedGoogle Scholar

Buist AS, Sexton GJ, Nagy JM, Ross BB. 1976. The effect of smoking cessation and modification on lung function. Am Rev Respir Dis. 114(1):115–122. doi:10.1164/arrd.1976.114.1.115

 PubMedGoogle Scholar

Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. 2005. Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J. 26(5):835–845. doi:10.1183/09031936.05.00108904

 PubMed Web of Science ®Google Scholar

Carmella SG, Chen M, Han S, Briggs A, Jensen J, Hatsukami DK, Hecht SS. 2009. Effects of smoking cessation on eight urinary tobacco carcinogen and toxicant biomarkers. Chem Res Toxicol. 2012 Mar 1925(3):763–763. doi:10.1021/tx300048h

 Google Scholar

El-Deek SE, Makhlouf HA, Saleem TH, Mandour MA, Mohamed NA. 2013. Surfactant protein D, soluble intercellular adhesion molecule-1 and high-sensitivity C-reactive protein as biomarkers of chronic obstructive pulmonary disease. Med Princ Pract. 22(5):469–474. doi:10.1159/000349934

 PubMed Web of Science ®Google Scholar

Voulgari C, Katsilambros N, Tentolouris N. 2011. Smoking cessation predicts amelioration of microalbuminuria in newly diagnosed type 2 diabetes mellitus: a 1-year prospective study. Metabolism. 60(10):1456–1464. doi:10.1016/j.metabol.2011.02.014

 PubMed Web of Science ®Google Scholar

Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR, Bangdiwala S, Tyroler HA. 1989. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 79(1):8–15. doi:10.1161/01.cir.79.1.8

 PubMed Web of Science ®Google Scholar

Stubbe I, Eskilsson J, Nilsson-Ehle P. 1982. High-density lipoprotein concentrations increase after stopping smoking. Br Med J (Clin Res Ed)). 284(6328):1511–1513. doi:10.1136/bmj.284.6328.1511

 PubMedGoogle Scholar

Brischetto CS, Connor WE, Connor SL, Matarazzo JD. 1983. Plasma lipid and lipoprotein profiles of cigarette smokers from randomly selected families: enhancement of hyperlipidemia and depression of high-density lipoprotein. Am J Cardiol. 52(7):675–680. doi:10.1016/0002-9149(83)90396-x

 PubMed Web of Science ®Google Scholar

Tonstad S, Urdal P. 2002. Does short-term smoking cessation reduce plasma total homocysteine concentrations? Scand J Clin Lab Invest. 62(4):279–284. doi:10.1080/003655102760145834

 PubMed Web of Science ®Google Scholar

Andelid K, Bake B, Rak S, Lindén A, Rosengren A, Ekberg-Jansson A. 2007. Myeloperoxidase as a marker of increasing systemic inflammation in smokers without severe airway symptoms. Respir Med. 101(5):888–895. doi:10.1016/j.rmed.2006.09.023

 PubMed Web of Science ®Google Scholar

Sinha S, Luben RN, Welch A, Bingham S, Wareham NJ, Day NE, Khaw KT. 2005. Fibrinogen and cigarette smoking in men and women in the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population. Eur J Cardiovasc Prev Rehabil. 12(2):144–150. doi:10.1097/01.hjr.0000140719.09768.e2

 PubMedGoogle Scholar

Caponnetto P, Russo C, Di Maria A, Morjaria JB, Barton S, Guarino F, Basile E, Proiti M, Bertino G, Cacciola RR, et al. 2011. Circulating endothelial-coagulative activation markers after smoking cessation: a 12-month observational study. Eur J Clin Invest. 41(6):616–626. doi:10.1111/j.1365-2362.2010.02449.x

 PubMed Web of Science ®Google Scholar

Morita H, Ikeda H, Haramaki N, Eguchi H, Imaizumi T. 2005. Only two-week smoking cessation improves platelet aggregability and intraplatelet redox imbalance of long-term smokers. J Am Coll Cardiol. 45(4):589–594. doi:10.1016/j.jacc.2004.10.061

 PubMed Web of Science ®Google Scholar

Tan XJ, Jiao GP, Ren YJ, Gao XR, Ding Y, Wang XR, Xu H. 2008. Relationship between smoking and dyslipidemia in western Chinese elderly males. J Clin Lab Anal. 22(3):159–163. doi:10.1002/jcla.20235

 PubMed Web of Science ®Google Scholar

Data availability statement

The data generated in this study are not publicly available but are available upon reasonable request from the corresponding author. The study protocol and study results are disclosed on ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02649556).