Visit-to-visit cholesterol variability correlates with coronary atheroma progression and clinical outcomes

Visit-to-visit cholesterol variability correlates with coronary atheroma progression and clinical... Abstract Aims Utilizing serial intravascular ultrasonography (IVUS), we aimed to exam the association of intra-individual lipid variability, coronary atheroma progression, and clinical outcomes. Methods and results We performed a post hoc patient-level analysis of nine clinical trials involving 4976 patients with coronary artery disease who underwent serial coronary IVUS in the setting of a range of medical therapies. We assessed the associations between progression in percent atheroma volume (ΔPAV), clinical outcomes, and visit-to-visit lipid variability including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC)/HDL-C, and apolipoprotein B (ApoB). Variability of lipid parameters was measured using intra-individual standard deviation over 3, 6, 12, 18, and 24 months. Atherogenic lipoprotein variability significantly associated with ΔPAV [odds ratio (95% confidence interval; P-value), LDL-C: 1.09 (1.02, 1.17, P = 0.01); non-HDL-C: 1.10 (1.02, 1.18, P = 0.01); TC/HDL-C: 1.14 (1.06, 1.24, P = 0.001); ApoB: 1.13 (1.03, 1.24, P = 0.01)]. Survival curves revealed significant stepwise relationships between cumulative major adverse cardiovascular events and increasing quartiles of atherogenic lipoprotein variability at 24-months follow-up (log-rank P < 0.01 for all lipoproteins except HDL-C). Stronger associations were noted between achieved lipoprotein levels and ΔPAV [LDL-C: 1.27 (1.17, 1.39; P < 0.001); non-HDL-C: 1.32 (1.21, 1.45; P < 0.001); TC/HDL-C: 1.31 (1.19, 1.45; P < 0.001); ApoB: 1.20 (1.07, 1.35; P = 0.003)]. Conclusion Greater visit-to-visit variability in atherogenic lipoprotein levels significantly associates with coronary atheroma progression and clinical outcomes, although the association between achieved atherogenic lipoproteins and atheroma progression appears stronger. These data highlight the importance of achieving low and consistent atherogenic lipoprotein levels to promote plaque regression and improve clinical outcomes. Cholesterol , Lipoproteins , Prevention Introduction Visit-to-visit low-density lipoprotein cholesterol (LDL-C) variability has recently sparked interest as a possible predictor of cardiovascular events. Recent analyses of large clinical trials and population cohorts have demonstrated that higher lipoprotein cholesterol variability is associated with death, myocardial infarction (MI), stroke, and cognitive dysfunction.1–3 These findings appear to be independent of the treatment effect with 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors (statins), suggesting cholesterol variability as a possible marker of residual risk for adverse outcomes among high-risk patients. However, mechanisms linking LDL-C variability and increased cardiovascular risk remain unknown, and whether these findings can be extended to a broader lipoprotein profile has yet to be reported. Furthermore, whether lipoprotein variability represents a broader systemic epiphenomenon or is directly related to a proatherosclerotic process remains unexplored. Intravascular ultrasonography (IVUS) provides precise and reproducible volumetric measurements of coronary atheroma.4 Serial IVUS examination permits the examination of the effects of intra-individual lipid variability upon coronary atheroma progression. We tested the hypothesis that intra-individual lipoprotein variability [measured as LDL-C, non-high density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) to HDL-C ratio or TC/HDL-C, and apolipoprotein B (ApoB)] associates with coronary atheroma progression–regression and clinical outcomes. Methods Study population This analysis included all participants in nine clinical trials assessing the impact of medical therapies on serial changes in coronary atheroma burden using IVUS. Included in this analysis were trials assessing intensive lipid lowering with statins [REVERSAL (Reversal of Atherosclerosis With Aggressive Lipid Lowering), ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular-Ultrasound Derived Indices of Coronary Atheroma Burden), and SATURN (The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin vs. Atorvastatin)],5–7 antihypertensive therapies [AQUARIUS (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) and NORMALISE (Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation)],8,9 the antiatherosclerotic efficacy of acyl-coenzyme A: cholesteryl ester transfer protein inhibition [ACTIVATE (ACAT Intravascular Atherosclerosis Treatment Evaluation)],10 cholesteryl ester transfer protein inhibition [ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)],11 endocannibinoid receptor antagonism [STRADIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—The Intravascular Ultrasound Study)],12 and the peroxisome proliferator-activated receptor gamma agonism [PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation)].13 Lipoprotein variability measurements Beyond descriptive statistics for the whole population, subjects with 3 or 4 respective post-baseline lipoprotein measurements were included for all other analyses. Variability was assessed across 3, 6, 12, 18, and 24 month measures. Visit-to-visit variability was defined as variability in lipoprotein values between visits. Previous posthoc analyses of clinical trials evaluating cholesterol variability used similar cut-offs to assess variability.1,2 For patients with missing lipoprotein values at any specific visit, available values at other time points were used to calculate variability. Variability was measured in two ways: (i) standard deviation (SD) of lipoprotein levels and (ii) average successive variability, defined as the average absolute difference between successive values.1 Strong correlation between SD and average successive variability was demonstrated (Spearman correlation coefficient >0.9, P < 0.001 for all lipoprotein measurements). Therefore, SD was selected as the primary means of representing variability in this analysis. Acquisition and analysis of serial intravascular ultrasonography images The acquisition and serial analysis of IVUS images in each of these trials has been previously described in detail. Briefly, target vessels for imaging were selected if they contained no luminal stenosis of >50% angiographic severity within a segment of at least 30 mm length. Imaging was performed within the same coronary artery at baseline and at study completion, which ranged from 18 to 24 months. Imaging in all trials was screened by the Atherosclerosis Imaging Core Laboratory of the Cleveland Clinic Coordinating Center for Clinical Research (C5R). Patients meeting pre-specified requirements for image quality were eligible for randomization. An anatomically matched segment was defined at the two time points on the basis of proximal and distal side branches (fiduciary points). Cross-sectional images spaced precisely 1 mm part were selected for measurement. Leading edges of the lumen and external elastic membrane (EEM) were traced by manual planimetry. Plaque area was defined as the area occupied between these leading edges. The accuracy and reproducibility of this method have been reported previously.14 The percent atheroma volume (PAV) was determined by calculating the proportion of the entire vessel wall occupied by atherosclerotic plaque, throughout the segment of interest as follows:   PAV=Σ(EEMarea−Lumenarea)ΣEMMarea×100. Statistical analysis Continuous variables are reported as mean  ± SD. Categorical variables are reported as frequency and percent. A paired t-test was used to test if the mean change in lipids from baseline was different from zero. While adjusting for trial and baseline PAV, a mixed model was used to test if the least-squares mean annualized change in PAV from baseline was different from zero. Multivariable mixed models were constructed in order to assess the association of lipid variability and average on-treatment lipid values with annualized change in PAV (ΔPAV). Separate models were run for lipid variability and average follow-up lipid values due to multicollinearity. In order to compare regression coefficients across models, continuous data were first standardized to have a mean of 0 and a SD of 1, and then the models were run on this standardized data. Variables adjusted for in each model included baseline lipid, baseline PAV, region, number of follow-up measure for each respective lipid (3 vs. 4), age, gender, body mass index (BMI), diabetes, concomitant statin use, and clinical trial. Beta coefficients with 95% confidence intervals (CI) are reported. Similarly, logistic regression models were constructed to assess the association of lipid variability and average on-treatment lipid values with any plaque progression. The same standardization and adjustments were made in these models as above. Odds ratio with 95% CI are reported. The Kaplan–Meier (KM) curves illustrate the first incidence of major adverse cardiovascular event (MACE; defined as death, MI, stroke, urgent revascularization for acute coronary syndrome, and hospitalization for unstable angina) stratified by quartiles of the SD of each lipid. The data for the curves are censored at 24 months. The KM estimates of cumulative incidence of MACE are reported by quartile on each plot with log-rank tests performed to assess any difference in estimates among quartiles. Patients who received torcetrapib in ILLUSTRATE were excluded from the MACE sensitivity analysis due to torcetrapib’s toxic effect.15 All tests were two-tailed with a 0.05 significance level. Analyses were done using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Figures were made using R version 3.0.1 (The R Foundation for Statistical Computing, Vienna, Austria) and SigmaPlot version 11.0 (Systat Software Inc., San Jose, CA, USA). Results Table 1 describes baseline demographics, clinical characteristics, and medication use of the pooled study population (n = 4967). Mean age was 58 ± 9 years, 28% were women, 29% had diabetes mellitus, and the mean BMI was 30.8 ± 5.8 kg/m2. Notably, 74% received prior statin therapy, and concomitant (on-trial) rates of statins, aspirin, β-blockers, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were 96%, 94%, 76%, and 68%, respectively. Table 1 Patient characteristics   n = 4976  Age (years)  58 ± 9  Female, n (%)  1398 (28)  Caucasian, n (%)  4625 (93)  Body mass index (kg/m2)  30.8 ± 5.8  Current smoker, n (%)  1155 (25)  Medical history, n (%)     Hypertension  3864 (78)   Diabetes  1442 (29)   Hyperlipidaemia  3503 (70)   Congestive heart failure  167 (3)   History of MI  1448 (29)   History of CABG  110 (2)   History of PCI  1831 (40)   History of CVA  152 (3)   History of PVD  245 (5)  Medication use during trial, n (%)     Aspirin  4685 (94)   Beta blockers  3787 (76)   Ace inhibitors  2713 (55)   Angiotensin receptor blockers  1007 (20)   Calcium channel blockers  1938 (39)   Statin  4752 (96)    n = 4976  Age (years)  58 ± 9  Female, n (%)  1398 (28)  Caucasian, n (%)  4625 (93)  Body mass index (kg/m2)  30.8 ± 5.8  Current smoker, n (%)  1155 (25)  Medical history, n (%)     Hypertension  3864 (78)   Diabetes  1442 (29)   Hyperlipidaemia  3503 (70)   Congestive heart failure  167 (3)   History of MI  1448 (29)   History of CABG  110 (2)   History of PCI  1831 (40)   History of CVA  152 (3)   History of PVD  245 (5)  Medication use during trial, n (%)     Aspirin  4685 (94)   Beta blockers  3787 (76)   Ace inhibitors  2713 (55)   Angiotensin receptor blockers  1007 (20)   Calcium channel blockers  1938 (39)   Statin  4752 (96)  Values are presented as mean ± standard deviation or n (%). CABG, coronary artery bypass graft; CVA, cerebral vascular accident; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease. Table 1 Patient characteristics   n = 4976  Age (years)  58 ± 9  Female, n (%)  1398 (28)  Caucasian, n (%)  4625 (93)  Body mass index (kg/m2)  30.8 ± 5.8  Current smoker, n (%)  1155 (25)  Medical history, n (%)     Hypertension  3864 (78)   Diabetes  1442 (29)   Hyperlipidaemia  3503 (70)   Congestive heart failure  167 (3)   History of MI  1448 (29)   History of CABG  110 (2)   History of PCI  1831 (40)   History of CVA  152 (3)   History of PVD  245 (5)  Medication use during trial, n (%)     Aspirin  4685 (94)   Beta blockers  3787 (76)   Ace inhibitors  2713 (55)   Angiotensin receptor blockers  1007 (20)   Calcium channel blockers  1938 (39)   Statin  4752 (96)    n = 4976  Age (years)  58 ± 9  Female, n (%)  1398 (28)  Caucasian, n (%)  4625 (93)  Body mass index (kg/m2)  30.8 ± 5.8  Current smoker, n (%)  1155 (25)  Medical history, n (%)     Hypertension  3864 (78)   Diabetes  1442 (29)   Hyperlipidaemia  3503 (70)   Congestive heart failure  167 (3)   History of MI  1448 (29)   History of CABG  110 (2)   History of PCI  1831 (40)   History of CVA  152 (3)   History of PVD  245 (5)  Medication use during trial, n (%)     Aspirin  4685 (94)   Beta blockers  3787 (76)   Ace inhibitors  2713 (55)   Angiotensin receptor blockers  1007 (20)   Calcium channel blockers  1938 (39)   Statin  4752 (96)  Values are presented as mean ± standard deviation or n (%). CABG, coronary artery bypass graft; CVA, cerebral vascular accident; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease. Table 2 describes baseline and follow-up for lipid measurements and plaque volume. In the overall population, the achieved levels of LDL-C, non-HDL-C, HDL-C, TC-HDL-C, ApoB, and haemoglobin A1c were 83 ± 28 mg/dL, 111 ± 33 mg/dL, 48 ± 15 mg/dL, 3.6 ± 1.2, 80 ± 25, and 6.3 ± 1.2, respectively. Overall, there was no net significant annualized change in PAV (least-squares mean ± standard error: 0.14 ± 0.15, P = 0.38). Table 3 summarizes trial characteristics as well as the mean intra-individual SD of each lipoprotein variable stratified by clinical trial. Table 2 Lipid and intravascular ultrasonography measurements at baseline and follow-up (n = 4976) Lipid measurements  Baseline  Follow-up  P-valuea µ(Δ) = 0  LDL-C  106 ± 35  83 ± 28  <0.001  Non-HDL-C  136 ± 41  111 ± 33  <0.001  HDL-C  43 ± 12  48 ± 15  <0.001  TC/HDL-C  4.4 ± 1.5  3.6 ± 1.2  <0.001  Apo B  100 ± 34  80 ± 25  <0.001  HbA1c  6.4 ± 1.2  6.3 ± 1.2  0.46  IVUS         PAV  38 ± 9  38 ± 9  0.38b  Lipid measurements  Baseline  Follow-up  P-valuea µ(Δ) = 0  LDL-C  106 ± 35  83 ± 28  <0.001  Non-HDL-C  136 ± 41  111 ± 33  <0.001  HDL-C  43 ± 12  48 ± 15  <0.001  TC/HDL-C  4.4 ± 1.5  3.6 ± 1.2  <0.001  Apo B  100 ± 34  80 ± 25  <0.001  HbA1c  6.4 ± 1.2  6.3 ± 1.2  0.46  IVUS         PAV  38 ± 9  38 ± 9  0.38b  Values are presented as mean ± standard deviation. Apo B, apolipoprotein B cholesterol; HDL-C, high density lipoprotein cholesterol; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; PAV, percent atheroma volume; TC, total cholesterol. a Tests if the mean of the average follow-up change from baseline is statistically different from zero. b Adjusted for baseline PAV and trial. Table 2 Lipid and intravascular ultrasonography measurements at baseline and follow-up (n = 4976) Lipid measurements  Baseline  Follow-up  P-valuea µ(Δ) = 0  LDL-C  106 ± 35  83 ± 28  <0.001  Non-HDL-C  136 ± 41  111 ± 33  <0.001  HDL-C  43 ± 12  48 ± 15  <0.001  TC/HDL-C  4.4 ± 1.5  3.6 ± 1.2  <0.001  Apo B  100 ± 34  80 ± 25  <0.001  HbA1c  6.4 ± 1.2  6.3 ± 1.2  0.46  IVUS         PAV  38 ± 9  38 ± 9  0.38b  Lipid measurements  Baseline  Follow-up  P-valuea µ(Δ) = 0  LDL-C  106 ± 35  83 ± 28  <0.001  Non-HDL-C  136 ± 41  111 ± 33  <0.001  HDL-C  43 ± 12  48 ± 15  <0.001  TC/HDL-C  4.4 ± 1.5  3.6 ± 1.2  <0.001  Apo B  100 ± 34  80 ± 25  <0.001  HbA1c  6.4 ± 1.2  6.3 ± 1.2  0.46  IVUS         PAV  38 ± 9  38 ± 9  0.38b  Values are presented as mean ± standard deviation. Apo B, apolipoprotein B cholesterol; HDL-C, high density lipoprotein cholesterol; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; PAV, percent atheroma volume; TC, total cholesterol. a Tests if the mean of the average follow-up change from baseline is statistically different from zero. b Adjusted for baseline PAV and trial. Table 3 Description and standard deviation of lipoproteins by trial   n  Treatment arms  Time points available  Variability   (n where 3 or 4 time points)           SD of LDL-C  SD of non-HDL-C  SD of HDL-C  SD of TC/HDL-C  SD of Apo B  REVERSAL  502  Pravastatin  3, 6, 12, 18  13.3 ± 9.3  15.8 ± 12.1  4.1 ± 2.5  0.5 ± 0.4  11.8 ± 7.5  Atorvastatin  (n = 500)  (n = 500)  (n = 500)  (n = 500)  (n = 500)  ASTEROID  349  Rosuvastatin  3, 12, 24  10.5 ± 10.9  12.9 ± 11.9  4.6 ± 3.9  0.3 ± 0.3  10.5 ± 10.1  (n = 338)  (n = 345)  (n = 345)  (n = 345)  (n = 161)  SATURN  1039  Atorvastatin  6, 12, 18, 24  11.1 ± 9.4  13.3 ± 10.6  4.6 ± 2.7  0.3 ± 0.3  8.9 ± 6.5  Rosuvastatin  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1020)  AQUARIUS  458  Aliskiren  6, 12, 18, 24  15.8 ± 11.5  17.3 ± 12.7  4.6 ± 2.9  0.4 ± 0.3  -  Placebo  (n = 452)  (n = 452)  (n = 452)  (n = 452)  NORMALISE  274  Amlodipine  6, 12, 18, 24  17.5 ± 12.0  20.5 ± 15.3  5.0 ± 3.1  0.8 ± 0.6  -  Enalapril  (n = 243)  (n = 263)  (n = 263)  (n = 263)  Placebo  ACTIVATE  408  Pactimibe  3, 6, 12, 18  15.7 ± 10.3  19.1 ± 13.2  4.0 ± 2.5  0.5 ± 0.4  13.3 ± 9.7  Placebo  (n = 394)  (n = 405)  (n = 405)  (n = 405)  (n = 364)a  ILLUSTRATE  910  Atorvastatin  3, 6, 12, 18, 24  11.4 ± 7.6  13.4 ± 11.4  5.5 ± 3.7  0.4 ± 0.3  -  Atorvastatin + Torcetrapib  (n = 143)  (n = 138)  (n = 138)  (n = 138)  STRADIVARIUS  676  Rimonabant  6, 12, 18  15.3 ± 12.5  17.7 ± 14.2  4.6 ± 3.2  0.5 ± 0.6  -  Placebo  (n = 404)  (n = 404)  (n = 413)  (n = 404)  PERISCOPE  360  Pioglitazone  6, 12, 18  16.9 ± 13.0  19.8 ± 14.8  4.6 ± 3.5  0.5 ± 0.5  11.0 ± 8.0  Glimepiride  (n = 334)  (n = 326)  (n = 326)  (n = 326)  (n = 302)  Total  4976      13.7 ± 10.9  16.2 ± 12.9  4.5 ± 3.0  0.4 ± 0.4  10.6 ± 8.0  (n = 3835)  (n = 3860)  (n = 3869)  (n = 3860)  (n = 2347)    n  Treatment arms  Time points available  Variability   (n where 3 or 4 time points)           SD of LDL-C  SD of non-HDL-C  SD of HDL-C  SD of TC/HDL-C  SD of Apo B  REVERSAL  502  Pravastatin  3, 6, 12, 18  13.3 ± 9.3  15.8 ± 12.1  4.1 ± 2.5  0.5 ± 0.4  11.8 ± 7.5  Atorvastatin  (n = 500)  (n = 500)  (n = 500)  (n = 500)  (n = 500)  ASTEROID  349  Rosuvastatin  3, 12, 24  10.5 ± 10.9  12.9 ± 11.9  4.6 ± 3.9  0.3 ± 0.3  10.5 ± 10.1  (n = 338)  (n = 345)  (n = 345)  (n = 345)  (n = 161)  SATURN  1039  Atorvastatin  6, 12, 18, 24  11.1 ± 9.4  13.3 ± 10.6  4.6 ± 2.7  0.3 ± 0.3  8.9 ± 6.5  Rosuvastatin  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1020)  AQUARIUS  458  Aliskiren  6, 12, 18, 24  15.8 ± 11.5  17.3 ± 12.7  4.6 ± 2.9  0.4 ± 0.3  -  Placebo  (n = 452)  (n = 452)  (n = 452)  (n = 452)  NORMALISE  274  Amlodipine  6, 12, 18, 24  17.5 ± 12.0  20.5 ± 15.3  5.0 ± 3.1  0.8 ± 0.6  -  Enalapril  (n = 243)  (n = 263)  (n = 263)  (n = 263)  Placebo  ACTIVATE  408  Pactimibe  3, 6, 12, 18  15.7 ± 10.3  19.1 ± 13.2  4.0 ± 2.5  0.5 ± 0.4  13.3 ± 9.7  Placebo  (n = 394)  (n = 405)  (n = 405)  (n = 405)  (n = 364)a  ILLUSTRATE  910  Atorvastatin  3, 6, 12, 18, 24  11.4 ± 7.6  13.4 ± 11.4  5.5 ± 3.7  0.4 ± 0.3  -  Atorvastatin + Torcetrapib  (n = 143)  (n = 138)  (n = 138)  (n = 138)  STRADIVARIUS  676  Rimonabant  6, 12, 18  15.3 ± 12.5  17.7 ± 14.2  4.6 ± 3.2  0.5 ± 0.6  -  Placebo  (n = 404)  (n = 404)  (n = 413)  (n = 404)  PERISCOPE  360  Pioglitazone  6, 12, 18  16.9 ± 13.0  19.8 ± 14.8  4.6 ± 3.5  0.5 ± 0.5  11.0 ± 8.0  Glimepiride  (n = 334)  (n = 326)  (n = 326)  (n = 326)  (n = 302)  Total  4976      13.7 ± 10.9  16.2 ± 12.9  4.5 ± 3.0  0.4 ± 0.4  10.6 ± 8.0  (n = 3835)  (n = 3860)  (n = 3869)  (n = 3860)  (n = 2347)  Apo B, apolipoprotein B cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol. a No 3-month data available for Apo B. Table 3 Description and standard deviation of lipoproteins by trial   n  Treatment arms  Time points available  Variability   (n where 3 or 4 time points)           SD of LDL-C  SD of non-HDL-C  SD of HDL-C  SD of TC/HDL-C  SD of Apo B  REVERSAL  502  Pravastatin  3, 6, 12, 18  13.3 ± 9.3  15.8 ± 12.1  4.1 ± 2.5  0.5 ± 0.4  11.8 ± 7.5  Atorvastatin  (n = 500)  (n = 500)  (n = 500)  (n = 500)  (n = 500)  ASTEROID  349  Rosuvastatin  3, 12, 24  10.5 ± 10.9  12.9 ± 11.9  4.6 ± 3.9  0.3 ± 0.3  10.5 ± 10.1  (n = 338)  (n = 345)  (n = 345)  (n = 345)  (n = 161)  SATURN  1039  Atorvastatin  6, 12, 18, 24  11.1 ± 9.4  13.3 ± 10.6  4.6 ± 2.7  0.3 ± 0.3  8.9 ± 6.5  Rosuvastatin  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1020)  AQUARIUS  458  Aliskiren  6, 12, 18, 24  15.8 ± 11.5  17.3 ± 12.7  4.6 ± 2.9  0.4 ± 0.3  -  Placebo  (n = 452)  (n = 452)  (n = 452)  (n = 452)  NORMALISE  274  Amlodipine  6, 12, 18, 24  17.5 ± 12.0  20.5 ± 15.3  5.0 ± 3.1  0.8 ± 0.6  -  Enalapril  (n = 243)  (n = 263)  (n = 263)  (n = 263)  Placebo  ACTIVATE  408  Pactimibe  3, 6, 12, 18  15.7 ± 10.3  19.1 ± 13.2  4.0 ± 2.5  0.5 ± 0.4  13.3 ± 9.7  Placebo  (n = 394)  (n = 405)  (n = 405)  (n = 405)  (n = 364)a  ILLUSTRATE  910  Atorvastatin  3, 6, 12, 18, 24  11.4 ± 7.6  13.4 ± 11.4  5.5 ± 3.7  0.4 ± 0.3  -  Atorvastatin + Torcetrapib  (n = 143)  (n = 138)  (n = 138)  (n = 138)  STRADIVARIUS  676  Rimonabant  6, 12, 18  15.3 ± 12.5  17.7 ± 14.2  4.6 ± 3.2  0.5 ± 0.6  -  Placebo  (n = 404)  (n = 404)  (n = 413)  (n = 404)  PERISCOPE  360  Pioglitazone  6, 12, 18  16.9 ± 13.0  19.8 ± 14.8  4.6 ± 3.5  0.5 ± 0.5  11.0 ± 8.0  Glimepiride  (n = 334)  (n = 326)  (n = 326)  (n = 326)  (n = 302)  Total  4976      13.7 ± 10.9  16.2 ± 12.9  4.5 ± 3.0  0.4 ± 0.4  10.6 ± 8.0  (n = 3835)  (n = 3860)  (n = 3869)  (n = 3860)  (n = 2347)    n  Treatment arms  Time points available  Variability   (n where 3 or 4 time points)           SD of LDL-C  SD of non-HDL-C  SD of HDL-C  SD of TC/HDL-C  SD of Apo B  REVERSAL  502  Pravastatin  3, 6, 12, 18  13.3 ± 9.3  15.8 ± 12.1  4.1 ± 2.5  0.5 ± 0.4  11.8 ± 7.5  Atorvastatin  (n = 500)  (n = 500)  (n = 500)  (n = 500)  (n = 500)  ASTEROID  349  Rosuvastatin  3, 12, 24  10.5 ± 10.9  12.9 ± 11.9  4.6 ± 3.9  0.3 ± 0.3  10.5 ± 10.1  (n = 338)  (n = 345)  (n = 345)  (n = 345)  (n = 161)  SATURN  1039  Atorvastatin  6, 12, 18, 24  11.1 ± 9.4  13.3 ± 10.6  4.6 ± 2.7  0.3 ± 0.3  8.9 ± 6.5  Rosuvastatin  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1020)  AQUARIUS  458  Aliskiren  6, 12, 18, 24  15.8 ± 11.5  17.3 ± 12.7  4.6 ± 2.9  0.4 ± 0.3  -  Placebo  (n = 452)  (n = 452)  (n = 452)  (n = 452)  NORMALISE  274  Amlodipine  6, 12, 18, 24  17.5 ± 12.0  20.5 ± 15.3  5.0 ± 3.1  0.8 ± 0.6  -  Enalapril  (n = 243)  (n = 263)  (n = 263)  (n = 263)  Placebo  ACTIVATE  408  Pactimibe  3, 6, 12, 18  15.7 ± 10.3  19.1 ± 13.2  4.0 ± 2.5  0.5 ± 0.4  13.3 ± 9.7  Placebo  (n = 394)  (n = 405)  (n = 405)  (n = 405)  (n = 364)a  ILLUSTRATE  910  Atorvastatin  3, 6, 12, 18, 24  11.4 ± 7.6  13.4 ± 11.4  5.5 ± 3.7  0.4 ± 0.3  -  Atorvastatin + Torcetrapib  (n = 143)  (n = 138)  (n = 138)  (n = 138)  STRADIVARIUS  676  Rimonabant  6, 12, 18  15.3 ± 12.5  17.7 ± 14.2  4.6 ± 3.2  0.5 ± 0.6  -  Placebo  (n = 404)  (n = 404)  (n = 413)  (n = 404)  PERISCOPE  360  Pioglitazone  6, 12, 18  16.9 ± 13.0  19.8 ± 14.8  4.6 ± 3.5  0.5 ± 0.5  11.0 ± 8.0  Glimepiride  (n = 334)  (n = 326)  (n = 326)  (n = 326)  (n = 302)  Total  4976      13.7 ± 10.9  16.2 ± 12.9  4.5 ± 3.0  0.4 ± 0.4  10.6 ± 8.0  (n = 3835)  (n = 3860)  (n = 3869)  (n = 3860)  (n = 2347)  Apo B, apolipoprotein B cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol. a No 3-month data available for Apo B. Table 4 describes, in separate models, the relationship of annualized change in PAV with lipoprotein variability and average on-treatment lipoprotein values. The SD of atherogenic lipid measurements were significantly associated with PAV progression [β (95% CI), LDL-C: 0.052 (0.024, 0.079), P < 0.001; non-HDL-C: 0.049 (0.021, 0.078), P < 0.001; TC/HDL-C: 0.064 (0.031, 0.096), P < 0.001; ApoB 0.051 (0.016, 0.086), P = 0.004]. There was no significant association between changes in PAV and HDL-C variability [−0.018 (−0.045, 0.009), P = 0.19]. Table 4 Standardized association of lipid variability and average on-treatment value with annualized change in percent atheroma volume   Variability (SD) and ΔPAV   On-treatment value (Avg) and ΔPAV     Standardized  P-value  Standardized  P-value  β (95% CI)  β (95% CI)  LDL-C           Overall population  0.052 (0.024, 0.079)  <0.001  0.119 (0.085, 0.154)  <0.001   Avg On-Tx ≥70 mg/dL  0.039 (0.008, 0.071)  0.015  0.130 (0.079, 0.181)  <0.001   Avg On-Tx <70 mg/dL  0.066 (−0.010, 0.142)  0.09  0.144 (0.032, 0.257)  0.01  Non-HDL-C           Overall population  0.049 (0.021, 0.078)  <0.001  0.141 (0.106, 0.177)  <0.001   Avg On-Tx ≥100 mg/dL  0.021 (−0.013, 0.054)  0.23  0.164 (0.107, 0.221)  <0.001   Avg On-Tx <100 mg/dL  0.071 (0.001, 0.141)  0.046  0.061 (−0.037, 0.159)  0.22  HDL-C           Overall population  −0.018 (−0.045, 0.009)  0.19  −0.075 (−0.119, −0.032)  <0.001   Avg On-Tx ≥ median  −0.013 (−0.044, 0.018)  0.41  −0.081 (−0.138, −0.024)  0.006   Avg On-Tx < median  −0.014 (−0.068, 0.041)  0.62  −0.041 (−0.162, 0.080)  0.50  TC/HDL-C           Overall population  0.064 (0.031, 0.096)  <0.001  0.150 (0.110, 0.190)  <0.001   Avg On-Tx ≥ median  0.033 (−0.005, 0.071)  0.091  0.116 (0.057, 0.176)  <0.001   Avg On-Tx < median  0.075 (−0.002, 0.152)  0.06  0.113 (0.001, 0.224)  0.048  Apo B           Overall population  0.051 (0.016, 0.086)  0.004  0.092 (0.045, 0.138)  <0.001   Avg On-Tx ≥ median  0.031 (−0.015, 0.077)  0.19  0.068 (−0.016, 0.152)  0.11   Avg On-Tx < median  0.046 (−0.012, 0.103)  0.12  0.048 (−0.059, 0.156)  0.38    Variability (SD) and ΔPAV   On-treatment value (Avg) and ΔPAV     Standardized  P-value  Standardized  P-value  β (95% CI)  β (95% CI)  LDL-C           Overall population  0.052 (0.024, 0.079)  <0.001  0.119 (0.085, 0.154)  <0.001   Avg On-Tx ≥70 mg/dL  0.039 (0.008, 0.071)  0.015  0.130 (0.079, 0.181)  <0.001   Avg On-Tx <70 mg/dL  0.066 (−0.010, 0.142)  0.09  0.144 (0.032, 0.257)  0.01  Non-HDL-C           Overall population  0.049 (0.021, 0.078)  <0.001  0.141 (0.106, 0.177)  <0.001   Avg On-Tx ≥100 mg/dL  0.021 (−0.013, 0.054)  0.23  0.164 (0.107, 0.221)  <0.001   Avg On-Tx <100 mg/dL  0.071 (0.001, 0.141)  0.046  0.061 (−0.037, 0.159)  0.22  HDL-C           Overall population  −0.018 (−0.045, 0.009)  0.19  −0.075 (−0.119, −0.032)  <0.001   Avg On-Tx ≥ median  −0.013 (−0.044, 0.018)  0.41  −0.081 (−0.138, −0.024)  0.006   Avg On-Tx < median  −0.014 (−0.068, 0.041)  0.62  −0.041 (−0.162, 0.080)  0.50  TC/HDL-C           Overall population  0.064 (0.031, 0.096)  <0.001  0.150 (0.110, 0.190)  <0.001   Avg On-Tx ≥ median  0.033 (−0.005, 0.071)  0.091  0.116 (0.057, 0.176)  <0.001   Avg On-Tx < median  0.075 (−0.002, 0.152)  0.06  0.113 (0.001, 0.224)  0.048  Apo B           Overall population  0.051 (0.016, 0.086)  0.004  0.092 (0.045, 0.138)  <0.001   Avg On-Tx ≥ median  0.031 (−0.015, 0.077)  0.19  0.068 (−0.016, 0.152)  0.11   Avg On-Tx < median  0.046 (−0.012, 0.103)  0.12  0.048 (−0.059, 0.156)  0.38  Adjusting for baseline PAV, baseline lipid, age, gender, body mass index, diabetes, concomitant statin use, region, number of follow-up lipid values (3 vs. 4), and trial. Apo B, apolipoprotein B cholesterol; Avg, average; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PAV percent atheroma volume; SD, standard deviation; TC, total cholesterol; Tx, treatment. Table 4 Standardized association of lipid variability and average on-treatment value with annualized change in percent atheroma volume   Variability (SD) and ΔPAV   On-treatment value (Avg) and ΔPAV     Standardized  P-value  Standardized  P-value  β (95% CI)  β (95% CI)  LDL-C           Overall population  0.052 (0.024, 0.079)  <0.001  0.119 (0.085, 0.154)  <0.001   Avg On-Tx ≥70 mg/dL  0.039 (0.008, 0.071)  0.015  0.130 (0.079, 0.181)  <0.001   Avg On-Tx <70 mg/dL  0.066 (−0.010, 0.142)  0.09  0.144 (0.032, 0.257)  0.01  Non-HDL-C           Overall population  0.049 (0.021, 0.078)  <0.001  0.141 (0.106, 0.177)  <0.001   Avg On-Tx ≥100 mg/dL  0.021 (−0.013, 0.054)  0.23  0.164 (0.107, 0.221)  <0.001   Avg On-Tx <100 mg/dL  0.071 (0.001, 0.141)  0.046  0.061 (−0.037, 0.159)  0.22  HDL-C           Overall population  −0.018 (−0.045, 0.009)  0.19  −0.075 (−0.119, −0.032)  <0.001   Avg On-Tx ≥ median  −0.013 (−0.044, 0.018)  0.41  −0.081 (−0.138, −0.024)  0.006   Avg On-Tx < median  −0.014 (−0.068, 0.041)  0.62  −0.041 (−0.162, 0.080)  0.50  TC/HDL-C           Overall population  0.064 (0.031, 0.096)  <0.001  0.150 (0.110, 0.190)  <0.001   Avg On-Tx ≥ median  0.033 (−0.005, 0.071)  0.091  0.116 (0.057, 0.176)  <0.001   Avg On-Tx < median  0.075 (−0.002, 0.152)  0.06  0.113 (0.001, 0.224)  0.048  Apo B           Overall population  0.051 (0.016, 0.086)  0.004  0.092 (0.045, 0.138)  <0.001   Avg On-Tx ≥ median  0.031 (−0.015, 0.077)  0.19  0.068 (−0.016, 0.152)  0.11   Avg On-Tx < median  0.046 (−0.012, 0.103)  0.12  0.048 (−0.059, 0.156)  0.38    Variability (SD) and ΔPAV   On-treatment value (Avg) and ΔPAV     Standardized  P-value  Standardized  P-value  β (95% CI)  β (95% CI)  LDL-C           Overall population  0.052 (0.024, 0.079)  <0.001  0.119 (0.085, 0.154)  <0.001   Avg On-Tx ≥70 mg/dL  0.039 (0.008, 0.071)  0.015  0.130 (0.079, 0.181)  <0.001   Avg On-Tx <70 mg/dL  0.066 (−0.010, 0.142)  0.09  0.144 (0.032, 0.257)  0.01  Non-HDL-C           Overall population  0.049 (0.021, 0.078)  <0.001  0.141 (0.106, 0.177)  <0.001   Avg On-Tx ≥100 mg/dL  0.021 (−0.013, 0.054)  0.23  0.164 (0.107, 0.221)  <0.001   Avg On-Tx <100 mg/dL  0.071 (0.001, 0.141)  0.046  0.061 (−0.037, 0.159)  0.22  HDL-C           Overall population  −0.018 (−0.045, 0.009)  0.19  −0.075 (−0.119, −0.032)  <0.001   Avg On-Tx ≥ median  −0.013 (−0.044, 0.018)  0.41  −0.081 (−0.138, −0.024)  0.006   Avg On-Tx < median  −0.014 (−0.068, 0.041)  0.62  −0.041 (−0.162, 0.080)  0.50  TC/HDL-C           Overall population  0.064 (0.031, 0.096)  <0.001  0.150 (0.110, 0.190)  <0.001   Avg On-Tx ≥ median  0.033 (−0.005, 0.071)  0.091  0.116 (0.057, 0.176)  <0.001   Avg On-Tx < median  0.075 (−0.002, 0.152)  0.06  0.113 (0.001, 0.224)  0.048  Apo B           Overall population  0.051 (0.016, 0.086)  0.004  0.092 (0.045, 0.138)  <0.001   Avg On-Tx ≥ median  0.031 (−0.015, 0.077)  0.19  0.068 (−0.016, 0.152)  0.11   Avg On-Tx < median  0.046 (−0.012, 0.103)  0.12  0.048 (−0.059, 0.156)  0.38  Adjusting for baseline PAV, baseline lipid, age, gender, body mass index, diabetes, concomitant statin use, region, number of follow-up lipid values (3 vs. 4), and trial. Apo B, apolipoprotein B cholesterol; Avg, average; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PAV percent atheroma volume; SD, standard deviation; TC, total cholesterol; Tx, treatment. Similarly, the average on-treatment values correlated significantly with PAV progression [LDL-C: 0.119 (0.085, 0.15), P < 0.001; non-HDL-C: 0.14 (0.11, 0.18), P < 0.001; TC/HDL-C: 0.15 (0.11, 0.19), P < 0.001; ApoB 0.09 (0.045, 0.14), P < 0.001]. In this case, average on-treatment HDL-C was significantly associated with PAV regression [−0.075 (−0.12, −0.032), P < 0.001]. Notably, there was not a significant association between LDL-C variability and annualized change in PAV in the population with achieved LDL-C levels <70 mg/dL [0.066 (−0.01, 0.14), P = 0.089]. In the same population however, there was a significant and stronger association between annualized change in PAV and average on-treatment LDL-C [0.14 (0.032, 0.26), P = 0.012]. Figure 1 illustrates the relationship of the binary outcome of PAV progression (or no progression) with lipid particle variability and average on-treatment value. Standard deviation of atherogenic lipid particles significantly associated with PAV progression [OR (95% CI), LDL-C: 1.09 (1.02, 1.17), P = 0.014; non-HDL-C: 1.10 (1.02, 1.18), P = 0.011; TC/HDL-C: 1.14 (1.06, 1.24), P = 0.001; ApoB: 1.13 (1.03, 1.24), P = 0.010]. There was however a more robust association observed between average on-treatment atherogenic lipoproteins and PAV progression [LDL-C: 1.27 (1.17, 1.39), P < 0.001; non-HDL-C: 1.32 (1.21, 1.45), P < 0.001; TC/HDL-C: 1.31 (1.19, 1.45), P < 0.001; ApoB: 1.20 (1.07, 1.35), P = 0.003]. Variability of HDL-C did not significantly associate with PAV progression [1.00 (0.93, 1.07), P = 0.95], and the relationship between average on-treatment HDL-C and PAV progression was borderline significant [0.88 (0.79, 0.99), P = 0.034]. Figure 1 View largeDownload slide Standardized association of variability and average on-treatment cholesterol with coronary atheroma progression. *Adjusting for baseline percent atheroma volume, lipid, age, sex, body mass index, diabetes, concomitant statin use, region, number of follow-up lipid values, and trial. BMI, body mass index; CI, confidence interval; OR, odds ratio; PAV, percent atheroma volume. Figure 1 View largeDownload slide Standardized association of variability and average on-treatment cholesterol with coronary atheroma progression. *Adjusting for baseline percent atheroma volume, lipid, age, sex, body mass index, diabetes, concomitant statin use, region, number of follow-up lipid values, and trial. BMI, body mass index; CI, confidence interval; OR, odds ratio; PAV, percent atheroma volume. Figure 2 illustrates the KM curves assessing MACE among patients stratified across quartiles of lipoprotein SD. At 24 months, there were significant stepwise relationships between cumulative MACE and increasing quartiles of atherogenic lipoprotein SD (KM estimates for quartiles 1–4, respectively: LDL-C: 5.7 vs. 7.3 vs. 7.7 vs. 10.9%, non-HDL-C: 5.1 vs. 7.0 vs. 9.5 vs. 10.5%, TC/HDL-C: 5.2 vs. 8.3 vs. 8.4 vs. 9.9%, ApoB: 3.9 vs. 6.0 vs. 8.8 vs. 11.4%, all log-rank P < 0.01). There was not a significant difference on incidence of MACE between any pair of SD quartiles of HDL-C (overall P = 0.30). Figure 2 View largeDownload slide Major adverse cardiovascular events among patients stratified across quartiles of lipoprotein variability. ApoB, apolipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation; TC, total cholesterol. Figure 2 View largeDownload slide Major adverse cardiovascular events among patients stratified across quartiles of lipoprotein variability. ApoB, apolipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation; TC, total cholesterol. For these analyses, similar results are seen when measuring lipoprotein variability using average successive variability, as presented in Supplementary material online, Tables SI and SII. Discussion In this posthoc patient-level analysis of nine clinical trials utilizing serial coronary IVUS, we demonstrate that greater visit-to-visit variability in atherogenic lipoprotein levels is independently associated with coronary atheroma progression and adverse cardiovascular outcomes. Our results confirm prior work demonstrating cholesterol variability as a predictor of cardiovascular events1–3 and further extend these findings across a range of atherogenic lipoprotein measurements including LDL-C, non-HDL-C, TC/HDL-C, and ApoB. The present analysis is the first to demonstrate that atherogenic lipoprotein variability is directly associated with a proatherosclerotic process, thereby providing a plausible mechanism linking this variability with the increased risk of cardiovascular events. The association however, between achieved lipoproteins and changes in coronary atheroma volume was comparatively stronger, highlighting the importance of aggressively lowering atherogenic lipoproteins in at-risk individuals. Recent analysis of the treating to new targets (TNT) trial demonstrated that LDL-C visit-to-visit variability predicts cardiovascular events independent of achieved LDL-C levels.1 These findings raised the possibility that LDL-C variability may represent a phenomenon contributing to residual risk among those with coronary artery disease already receiving optimal medical therapy. Subsequent analysis from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial demonstrated that higher visit-to-visit LDL-C variability was associated with lower neurocognitive performance, lower cerebral blood flow, and greater white matter hyperintensity on brain magnetic resonance imaging.2 Additionally, cholesterol variability was shown to associate with all-cause mortality, MI, and stroke in a large cohort broadly representative of the general Korean population.3 The association with cholesterol variability and cardiovascular outcomes now seems established; however, in order to target future interventions it is important to delineate pathophysiologic characteristics linking laboratory findings and clinical outcomes. Although the possibility for unmeasured confounders cannot be excluded in the present analysis, the clear association between atherogenic lipoprotein variability and plaque progression suggests a cholesterol-mediated proatherosclerotic effect as compared with a more general homeostatic imbalance affecting cardiovascular risk through other pathophysiologic mechanisms. The biological mechanisms underlying lipoprotein variability and the association with atheroma progression warrants further investigation. Multivariable modelling in the current analysis considered a number of potentially important factors including glucose control, BMI, concomitant statin use, and baseline lipid measurements. It is widely recognized that statins promote atheroma regression likely through reductions of the lipid, inflammatory, and necrotic plaque components.6 One hypothesis is that lipoprotein variability hinders lipid efflux from atheroma resulting in ongoing plaque volume progression (attenuating the effects of risk-modifying therapies); a process that significantly associates with incident cardiovascular events.16–19 Therapeutic means of lowering atherosclerotic and cardiovascular risk is fundamentally based on LDL-C reduction. However, among those who achieve low LDL-C levels, additional lipoproteins including TG, non-HDL-C, and Apo B contribute to residual risk. Furthermore, TC/HDL-C more accurately identifies atheroma progression and may better reflect atherogenic lipid particles, especially when LDL-C, Apo B, and non-HDL-C levels are discordant.20 The current analysis supports that variability of all lipoproteins is associated with plaque progression, and it is important to note the absence of association with HDL-C variability which is consistent with lack of benefit seen drug trials targeting HDL-C. The results of this analysis support the role of variability not only with LDL-C but also other atherogenic lipoproteins, and further research is required to better understand the mechanism underscoring these findings. The results of this analysis may have implications when considering the management of patients at risk for atherosclerotic heart disease. Among patients receiving statin therapy, current guidelines recommend periodic monitoring of lipid levels to assess adherence and therapeutic response.21–23 The present analysis suggests that serial lipid level monitoring is important to identify variability, in addition to statin hyporesponders, in order to intensify broader preventive therapy in higher-risk individuals.24 Also, intermittent statin dosing is an increasingly employed treatment strategy in statin intolerant patients based on effective LDL-C lowering in observational studies,25 yet these patients have substantially higher rates of cardiovascular events than those without statin intolerance.26 On-treatment atherogenic lipoprotein levels were found to harbour a more robust association with changes in atheroma volume, highlighting the well-established importance of aggressively lowering lipoprotein levels. These findings also lend further support to the ‘lower is better’ notion of LDL-C lowering, recently illustrated by the complementary findings of the GLAGOV and FOURIER randomized trials involving aggressive LDL-C with evolocumab.27,28 However, the present analysis also suggests that stability, in addition to reduction, may be an important consideration among statin intolerant patients who often require multiple medication regimen changes. Further studies are needed to assess the relationship between medication dosing, lipid reduction, lipid stability, and cardiovascular events. Several caveats of the current analysis warrant further consideration. This analysis is limited to patients enrolled in clinical trials with established coronary artery disease with an indication for coronary angiography and may not be applicable to those without documented atherosclerotic heart disease. Despite a rigorous statistical approach and relatively uniform inclusion/exclusion criteria in each trial, unmeasured confounding biasing the results cannot be excluded. Lipid measurements used in the variability assessment were obtained throughout the trial and therefore may introduce bias among those with non-fatal MACE prior to the end of follow-up. This limits the interpretation of the relationship between lipoprotein variability and MACE, and it is important emphasize that these findings represent an association and are thus considered hypothesis generating. On the other hand, the present data are unique in analysing a variety of lipoprotein variables across multiple clinical trials using appropriate statistical means to account for both confounders and the range of trialled therapies included in this analysis. Detailed pill counts were not a routine part of the serial IVUS trials included in this analysis; however, compliance rates were shown to be systematically >90% across these trials, thereby minimizing the issue of medication non-compliance significantly influencing the results. In conclusion, in patients with coronary artery disease receiving established medical therapies, greater visit-to-visit variability in atherogenic lipoprotein levels significantly associates with coronary atheroma progression and adverse clinical outcomes. These observations, coupled with stronger associations between achieved lipoprotein levels and plaque progression–regression, highlight the dual importance of not only aggressively lowering atherogenic lipoproteins levels but also achieving stable reductions. Further research is required to unravel mechanisms promoting lipoprotein variability, including its therapeutic implications. 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Visit-to-visit cholesterol variability correlates with coronary atheroma progression and clinical outcomes

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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0195-668X
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1522-9645
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10.1093/eurheartj/ehy209
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Abstract

Abstract Aims Utilizing serial intravascular ultrasonography (IVUS), we aimed to exam the association of intra-individual lipid variability, coronary atheroma progression, and clinical outcomes. Methods and results We performed a post hoc patient-level analysis of nine clinical trials involving 4976 patients with coronary artery disease who underwent serial coronary IVUS in the setting of a range of medical therapies. We assessed the associations between progression in percent atheroma volume (ΔPAV), clinical outcomes, and visit-to-visit lipid variability including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC)/HDL-C, and apolipoprotein B (ApoB). Variability of lipid parameters was measured using intra-individual standard deviation over 3, 6, 12, 18, and 24 months. Atherogenic lipoprotein variability significantly associated with ΔPAV [odds ratio (95% confidence interval; P-value), LDL-C: 1.09 (1.02, 1.17, P = 0.01); non-HDL-C: 1.10 (1.02, 1.18, P = 0.01); TC/HDL-C: 1.14 (1.06, 1.24, P = 0.001); ApoB: 1.13 (1.03, 1.24, P = 0.01)]. Survival curves revealed significant stepwise relationships between cumulative major adverse cardiovascular events and increasing quartiles of atherogenic lipoprotein variability at 24-months follow-up (log-rank P < 0.01 for all lipoproteins except HDL-C). Stronger associations were noted between achieved lipoprotein levels and ΔPAV [LDL-C: 1.27 (1.17, 1.39; P < 0.001); non-HDL-C: 1.32 (1.21, 1.45; P < 0.001); TC/HDL-C: 1.31 (1.19, 1.45; P < 0.001); ApoB: 1.20 (1.07, 1.35; P = 0.003)]. Conclusion Greater visit-to-visit variability in atherogenic lipoprotein levels significantly associates with coronary atheroma progression and clinical outcomes, although the association between achieved atherogenic lipoproteins and atheroma progression appears stronger. These data highlight the importance of achieving low and consistent atherogenic lipoprotein levels to promote plaque regression and improve clinical outcomes. Cholesterol , Lipoproteins , Prevention Introduction Visit-to-visit low-density lipoprotein cholesterol (LDL-C) variability has recently sparked interest as a possible predictor of cardiovascular events. Recent analyses of large clinical trials and population cohorts have demonstrated that higher lipoprotein cholesterol variability is associated with death, myocardial infarction (MI), stroke, and cognitive dysfunction.1–3 These findings appear to be independent of the treatment effect with 3-hydroxy-3-methylglutaryl coenzyme A (HMG Co-A) reductase inhibitors (statins), suggesting cholesterol variability as a possible marker of residual risk for adverse outcomes among high-risk patients. However, mechanisms linking LDL-C variability and increased cardiovascular risk remain unknown, and whether these findings can be extended to a broader lipoprotein profile has yet to be reported. Furthermore, whether lipoprotein variability represents a broader systemic epiphenomenon or is directly related to a proatherosclerotic process remains unexplored. Intravascular ultrasonography (IVUS) provides precise and reproducible volumetric measurements of coronary atheroma.4 Serial IVUS examination permits the examination of the effects of intra-individual lipid variability upon coronary atheroma progression. We tested the hypothesis that intra-individual lipoprotein variability [measured as LDL-C, non-high density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC) to HDL-C ratio or TC/HDL-C, and apolipoprotein B (ApoB)] associates with coronary atheroma progression–regression and clinical outcomes. Methods Study population This analysis included all participants in nine clinical trials assessing the impact of medical therapies on serial changes in coronary atheroma burden using IVUS. Included in this analysis were trials assessing intensive lipid lowering with statins [REVERSAL (Reversal of Atherosclerosis With Aggressive Lipid Lowering), ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular-Ultrasound Derived Indices of Coronary Atheroma Burden), and SATURN (The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin vs. Atorvastatin)],5–7 antihypertensive therapies [AQUARIUS (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) and NORMALISE (Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation)],8,9 the antiatherosclerotic efficacy of acyl-coenzyme A: cholesteryl ester transfer protein inhibition [ACTIVATE (ACAT Intravascular Atherosclerosis Treatment Evaluation)],10 cholesteryl ester transfer protein inhibition [ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation)],11 endocannibinoid receptor antagonism [STRADIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant—The Intravascular Ultrasound Study)],12 and the peroxisome proliferator-activated receptor gamma agonism [PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation)].13 Lipoprotein variability measurements Beyond descriptive statistics for the whole population, subjects with 3 or 4 respective post-baseline lipoprotein measurements were included for all other analyses. Variability was assessed across 3, 6, 12, 18, and 24 month measures. Visit-to-visit variability was defined as variability in lipoprotein values between visits. Previous posthoc analyses of clinical trials evaluating cholesterol variability used similar cut-offs to assess variability.1,2 For patients with missing lipoprotein values at any specific visit, available values at other time points were used to calculate variability. Variability was measured in two ways: (i) standard deviation (SD) of lipoprotein levels and (ii) average successive variability, defined as the average absolute difference between successive values.1 Strong correlation between SD and average successive variability was demonstrated (Spearman correlation coefficient >0.9, P < 0.001 for all lipoprotein measurements). Therefore, SD was selected as the primary means of representing variability in this analysis. Acquisition and analysis of serial intravascular ultrasonography images The acquisition and serial analysis of IVUS images in each of these trials has been previously described in detail. Briefly, target vessels for imaging were selected if they contained no luminal stenosis of >50% angiographic severity within a segment of at least 30 mm length. Imaging was performed within the same coronary artery at baseline and at study completion, which ranged from 18 to 24 months. Imaging in all trials was screened by the Atherosclerosis Imaging Core Laboratory of the Cleveland Clinic Coordinating Center for Clinical Research (C5R). Patients meeting pre-specified requirements for image quality were eligible for randomization. An anatomically matched segment was defined at the two time points on the basis of proximal and distal side branches (fiduciary points). Cross-sectional images spaced precisely 1 mm part were selected for measurement. Leading edges of the lumen and external elastic membrane (EEM) were traced by manual planimetry. Plaque area was defined as the area occupied between these leading edges. The accuracy and reproducibility of this method have been reported previously.14 The percent atheroma volume (PAV) was determined by calculating the proportion of the entire vessel wall occupied by atherosclerotic plaque, throughout the segment of interest as follows:   PAV=Σ(EEMarea−Lumenarea)ΣEMMarea×100. Statistical analysis Continuous variables are reported as mean  ± SD. Categorical variables are reported as frequency and percent. A paired t-test was used to test if the mean change in lipids from baseline was different from zero. While adjusting for trial and baseline PAV, a mixed model was used to test if the least-squares mean annualized change in PAV from baseline was different from zero. Multivariable mixed models were constructed in order to assess the association of lipid variability and average on-treatment lipid values with annualized change in PAV (ΔPAV). Separate models were run for lipid variability and average follow-up lipid values due to multicollinearity. In order to compare regression coefficients across models, continuous data were first standardized to have a mean of 0 and a SD of 1, and then the models were run on this standardized data. Variables adjusted for in each model included baseline lipid, baseline PAV, region, number of follow-up measure for each respective lipid (3 vs. 4), age, gender, body mass index (BMI), diabetes, concomitant statin use, and clinical trial. Beta coefficients with 95% confidence intervals (CI) are reported. Similarly, logistic regression models were constructed to assess the association of lipid variability and average on-treatment lipid values with any plaque progression. The same standardization and adjustments were made in these models as above. Odds ratio with 95% CI are reported. The Kaplan–Meier (KM) curves illustrate the first incidence of major adverse cardiovascular event (MACE; defined as death, MI, stroke, urgent revascularization for acute coronary syndrome, and hospitalization for unstable angina) stratified by quartiles of the SD of each lipid. The data for the curves are censored at 24 months. The KM estimates of cumulative incidence of MACE are reported by quartile on each plot with log-rank tests performed to assess any difference in estimates among quartiles. Patients who received torcetrapib in ILLUSTRATE were excluded from the MACE sensitivity analysis due to torcetrapib’s toxic effect.15 All tests were two-tailed with a 0.05 significance level. Analyses were done using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Figures were made using R version 3.0.1 (The R Foundation for Statistical Computing, Vienna, Austria) and SigmaPlot version 11.0 (Systat Software Inc., San Jose, CA, USA). Results Table 1 describes baseline demographics, clinical characteristics, and medication use of the pooled study population (n = 4967). Mean age was 58 ± 9 years, 28% were women, 29% had diabetes mellitus, and the mean BMI was 30.8 ± 5.8 kg/m2. Notably, 74% received prior statin therapy, and concomitant (on-trial) rates of statins, aspirin, β-blockers, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were 96%, 94%, 76%, and 68%, respectively. Table 1 Patient characteristics   n = 4976  Age (years)  58 ± 9  Female, n (%)  1398 (28)  Caucasian, n (%)  4625 (93)  Body mass index (kg/m2)  30.8 ± 5.8  Current smoker, n (%)  1155 (25)  Medical history, n (%)     Hypertension  3864 (78)   Diabetes  1442 (29)   Hyperlipidaemia  3503 (70)   Congestive heart failure  167 (3)   History of MI  1448 (29)   History of CABG  110 (2)   History of PCI  1831 (40)   History of CVA  152 (3)   History of PVD  245 (5)  Medication use during trial, n (%)     Aspirin  4685 (94)   Beta blockers  3787 (76)   Ace inhibitors  2713 (55)   Angiotensin receptor blockers  1007 (20)   Calcium channel blockers  1938 (39)   Statin  4752 (96)    n = 4976  Age (years)  58 ± 9  Female, n (%)  1398 (28)  Caucasian, n (%)  4625 (93)  Body mass index (kg/m2)  30.8 ± 5.8  Current smoker, n (%)  1155 (25)  Medical history, n (%)     Hypertension  3864 (78)   Diabetes  1442 (29)   Hyperlipidaemia  3503 (70)   Congestive heart failure  167 (3)   History of MI  1448 (29)   History of CABG  110 (2)   History of PCI  1831 (40)   History of CVA  152 (3)   History of PVD  245 (5)  Medication use during trial, n (%)     Aspirin  4685 (94)   Beta blockers  3787 (76)   Ace inhibitors  2713 (55)   Angiotensin receptor blockers  1007 (20)   Calcium channel blockers  1938 (39)   Statin  4752 (96)  Values are presented as mean ± standard deviation or n (%). CABG, coronary artery bypass graft; CVA, cerebral vascular accident; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease. Table 1 Patient characteristics   n = 4976  Age (years)  58 ± 9  Female, n (%)  1398 (28)  Caucasian, n (%)  4625 (93)  Body mass index (kg/m2)  30.8 ± 5.8  Current smoker, n (%)  1155 (25)  Medical history, n (%)     Hypertension  3864 (78)   Diabetes  1442 (29)   Hyperlipidaemia  3503 (70)   Congestive heart failure  167 (3)   History of MI  1448 (29)   History of CABG  110 (2)   History of PCI  1831 (40)   History of CVA  152 (3)   History of PVD  245 (5)  Medication use during trial, n (%)     Aspirin  4685 (94)   Beta blockers  3787 (76)   Ace inhibitors  2713 (55)   Angiotensin receptor blockers  1007 (20)   Calcium channel blockers  1938 (39)   Statin  4752 (96)    n = 4976  Age (years)  58 ± 9  Female, n (%)  1398 (28)  Caucasian, n (%)  4625 (93)  Body mass index (kg/m2)  30.8 ± 5.8  Current smoker, n (%)  1155 (25)  Medical history, n (%)     Hypertension  3864 (78)   Diabetes  1442 (29)   Hyperlipidaemia  3503 (70)   Congestive heart failure  167 (3)   History of MI  1448 (29)   History of CABG  110 (2)   History of PCI  1831 (40)   History of CVA  152 (3)   History of PVD  245 (5)  Medication use during trial, n (%)     Aspirin  4685 (94)   Beta blockers  3787 (76)   Ace inhibitors  2713 (55)   Angiotensin receptor blockers  1007 (20)   Calcium channel blockers  1938 (39)   Statin  4752 (96)  Values are presented as mean ± standard deviation or n (%). CABG, coronary artery bypass graft; CVA, cerebral vascular accident; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease. Table 2 describes baseline and follow-up for lipid measurements and plaque volume. In the overall population, the achieved levels of LDL-C, non-HDL-C, HDL-C, TC-HDL-C, ApoB, and haemoglobin A1c were 83 ± 28 mg/dL, 111 ± 33 mg/dL, 48 ± 15 mg/dL, 3.6 ± 1.2, 80 ± 25, and 6.3 ± 1.2, respectively. Overall, there was no net significant annualized change in PAV (least-squares mean ± standard error: 0.14 ± 0.15, P = 0.38). Table 3 summarizes trial characteristics as well as the mean intra-individual SD of each lipoprotein variable stratified by clinical trial. Table 2 Lipid and intravascular ultrasonography measurements at baseline and follow-up (n = 4976) Lipid measurements  Baseline  Follow-up  P-valuea µ(Δ) = 0  LDL-C  106 ± 35  83 ± 28  <0.001  Non-HDL-C  136 ± 41  111 ± 33  <0.001  HDL-C  43 ± 12  48 ± 15  <0.001  TC/HDL-C  4.4 ± 1.5  3.6 ± 1.2  <0.001  Apo B  100 ± 34  80 ± 25  <0.001  HbA1c  6.4 ± 1.2  6.3 ± 1.2  0.46  IVUS         PAV  38 ± 9  38 ± 9  0.38b  Lipid measurements  Baseline  Follow-up  P-valuea µ(Δ) = 0  LDL-C  106 ± 35  83 ± 28  <0.001  Non-HDL-C  136 ± 41  111 ± 33  <0.001  HDL-C  43 ± 12  48 ± 15  <0.001  TC/HDL-C  4.4 ± 1.5  3.6 ± 1.2  <0.001  Apo B  100 ± 34  80 ± 25  <0.001  HbA1c  6.4 ± 1.2  6.3 ± 1.2  0.46  IVUS         PAV  38 ± 9  38 ± 9  0.38b  Values are presented as mean ± standard deviation. Apo B, apolipoprotein B cholesterol; HDL-C, high density lipoprotein cholesterol; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; PAV, percent atheroma volume; TC, total cholesterol. a Tests if the mean of the average follow-up change from baseline is statistically different from zero. b Adjusted for baseline PAV and trial. Table 2 Lipid and intravascular ultrasonography measurements at baseline and follow-up (n = 4976) Lipid measurements  Baseline  Follow-up  P-valuea µ(Δ) = 0  LDL-C  106 ± 35  83 ± 28  <0.001  Non-HDL-C  136 ± 41  111 ± 33  <0.001  HDL-C  43 ± 12  48 ± 15  <0.001  TC/HDL-C  4.4 ± 1.5  3.6 ± 1.2  <0.001  Apo B  100 ± 34  80 ± 25  <0.001  HbA1c  6.4 ± 1.2  6.3 ± 1.2  0.46  IVUS         PAV  38 ± 9  38 ± 9  0.38b  Lipid measurements  Baseline  Follow-up  P-valuea µ(Δ) = 0  LDL-C  106 ± 35  83 ± 28  <0.001  Non-HDL-C  136 ± 41  111 ± 33  <0.001  HDL-C  43 ± 12  48 ± 15  <0.001  TC/HDL-C  4.4 ± 1.5  3.6 ± 1.2  <0.001  Apo B  100 ± 34  80 ± 25  <0.001  HbA1c  6.4 ± 1.2  6.3 ± 1.2  0.46  IVUS         PAV  38 ± 9  38 ± 9  0.38b  Values are presented as mean ± standard deviation. Apo B, apolipoprotein B cholesterol; HDL-C, high density lipoprotein cholesterol; IVUS, intravascular ultrasound; LDL-C, low-density lipoprotein cholesterol; PAV, percent atheroma volume; TC, total cholesterol. a Tests if the mean of the average follow-up change from baseline is statistically different from zero. b Adjusted for baseline PAV and trial. Table 3 Description and standard deviation of lipoproteins by trial   n  Treatment arms  Time points available  Variability   (n where 3 or 4 time points)           SD of LDL-C  SD of non-HDL-C  SD of HDL-C  SD of TC/HDL-C  SD of Apo B  REVERSAL  502  Pravastatin  3, 6, 12, 18  13.3 ± 9.3  15.8 ± 12.1  4.1 ± 2.5  0.5 ± 0.4  11.8 ± 7.5  Atorvastatin  (n = 500)  (n = 500)  (n = 500)  (n = 500)  (n = 500)  ASTEROID  349  Rosuvastatin  3, 12, 24  10.5 ± 10.9  12.9 ± 11.9  4.6 ± 3.9  0.3 ± 0.3  10.5 ± 10.1  (n = 338)  (n = 345)  (n = 345)  (n = 345)  (n = 161)  SATURN  1039  Atorvastatin  6, 12, 18, 24  11.1 ± 9.4  13.3 ± 10.6  4.6 ± 2.7  0.3 ± 0.3  8.9 ± 6.5  Rosuvastatin  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1020)  AQUARIUS  458  Aliskiren  6, 12, 18, 24  15.8 ± 11.5  17.3 ± 12.7  4.6 ± 2.9  0.4 ± 0.3  -  Placebo  (n = 452)  (n = 452)  (n = 452)  (n = 452)  NORMALISE  274  Amlodipine  6, 12, 18, 24  17.5 ± 12.0  20.5 ± 15.3  5.0 ± 3.1  0.8 ± 0.6  -  Enalapril  (n = 243)  (n = 263)  (n = 263)  (n = 263)  Placebo  ACTIVATE  408  Pactimibe  3, 6, 12, 18  15.7 ± 10.3  19.1 ± 13.2  4.0 ± 2.5  0.5 ± 0.4  13.3 ± 9.7  Placebo  (n = 394)  (n = 405)  (n = 405)  (n = 405)  (n = 364)a  ILLUSTRATE  910  Atorvastatin  3, 6, 12, 18, 24  11.4 ± 7.6  13.4 ± 11.4  5.5 ± 3.7  0.4 ± 0.3  -  Atorvastatin + Torcetrapib  (n = 143)  (n = 138)  (n = 138)  (n = 138)  STRADIVARIUS  676  Rimonabant  6, 12, 18  15.3 ± 12.5  17.7 ± 14.2  4.6 ± 3.2  0.5 ± 0.6  -  Placebo  (n = 404)  (n = 404)  (n = 413)  (n = 404)  PERISCOPE  360  Pioglitazone  6, 12, 18  16.9 ± 13.0  19.8 ± 14.8  4.6 ± 3.5  0.5 ± 0.5  11.0 ± 8.0  Glimepiride  (n = 334)  (n = 326)  (n = 326)  (n = 326)  (n = 302)  Total  4976      13.7 ± 10.9  16.2 ± 12.9  4.5 ± 3.0  0.4 ± 0.4  10.6 ± 8.0  (n = 3835)  (n = 3860)  (n = 3869)  (n = 3860)  (n = 2347)    n  Treatment arms  Time points available  Variability   (n where 3 or 4 time points)           SD of LDL-C  SD of non-HDL-C  SD of HDL-C  SD of TC/HDL-C  SD of Apo B  REVERSAL  502  Pravastatin  3, 6, 12, 18  13.3 ± 9.3  15.8 ± 12.1  4.1 ± 2.5  0.5 ± 0.4  11.8 ± 7.5  Atorvastatin  (n = 500)  (n = 500)  (n = 500)  (n = 500)  (n = 500)  ASTEROID  349  Rosuvastatin  3, 12, 24  10.5 ± 10.9  12.9 ± 11.9  4.6 ± 3.9  0.3 ± 0.3  10.5 ± 10.1  (n = 338)  (n = 345)  (n = 345)  (n = 345)  (n = 161)  SATURN  1039  Atorvastatin  6, 12, 18, 24  11.1 ± 9.4  13.3 ± 10.6  4.6 ± 2.7  0.3 ± 0.3  8.9 ± 6.5  Rosuvastatin  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1020)  AQUARIUS  458  Aliskiren  6, 12, 18, 24  15.8 ± 11.5  17.3 ± 12.7  4.6 ± 2.9  0.4 ± 0.3  -  Placebo  (n = 452)  (n = 452)  (n = 452)  (n = 452)  NORMALISE  274  Amlodipine  6, 12, 18, 24  17.5 ± 12.0  20.5 ± 15.3  5.0 ± 3.1  0.8 ± 0.6  -  Enalapril  (n = 243)  (n = 263)  (n = 263)  (n = 263)  Placebo  ACTIVATE  408  Pactimibe  3, 6, 12, 18  15.7 ± 10.3  19.1 ± 13.2  4.0 ± 2.5  0.5 ± 0.4  13.3 ± 9.7  Placebo  (n = 394)  (n = 405)  (n = 405)  (n = 405)  (n = 364)a  ILLUSTRATE  910  Atorvastatin  3, 6, 12, 18, 24  11.4 ± 7.6  13.4 ± 11.4  5.5 ± 3.7  0.4 ± 0.3  -  Atorvastatin + Torcetrapib  (n = 143)  (n = 138)  (n = 138)  (n = 138)  STRADIVARIUS  676  Rimonabant  6, 12, 18  15.3 ± 12.5  17.7 ± 14.2  4.6 ± 3.2  0.5 ± 0.6  -  Placebo  (n = 404)  (n = 404)  (n = 413)  (n = 404)  PERISCOPE  360  Pioglitazone  6, 12, 18  16.9 ± 13.0  19.8 ± 14.8  4.6 ± 3.5  0.5 ± 0.5  11.0 ± 8.0  Glimepiride  (n = 334)  (n = 326)  (n = 326)  (n = 326)  (n = 302)  Total  4976      13.7 ± 10.9  16.2 ± 12.9  4.5 ± 3.0  0.4 ± 0.4  10.6 ± 8.0  (n = 3835)  (n = 3860)  (n = 3869)  (n = 3860)  (n = 2347)  Apo B, apolipoprotein B cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol. a No 3-month data available for Apo B. Table 3 Description and standard deviation of lipoproteins by trial   n  Treatment arms  Time points available  Variability   (n where 3 or 4 time points)           SD of LDL-C  SD of non-HDL-C  SD of HDL-C  SD of TC/HDL-C  SD of Apo B  REVERSAL  502  Pravastatin  3, 6, 12, 18  13.3 ± 9.3  15.8 ± 12.1  4.1 ± 2.5  0.5 ± 0.4  11.8 ± 7.5  Atorvastatin  (n = 500)  (n = 500)  (n = 500)  (n = 500)  (n = 500)  ASTEROID  349  Rosuvastatin  3, 12, 24  10.5 ± 10.9  12.9 ± 11.9  4.6 ± 3.9  0.3 ± 0.3  10.5 ± 10.1  (n = 338)  (n = 345)  (n = 345)  (n = 345)  (n = 161)  SATURN  1039  Atorvastatin  6, 12, 18, 24  11.1 ± 9.4  13.3 ± 10.6  4.6 ± 2.7  0.3 ± 0.3  8.9 ± 6.5  Rosuvastatin  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1020)  AQUARIUS  458  Aliskiren  6, 12, 18, 24  15.8 ± 11.5  17.3 ± 12.7  4.6 ± 2.9  0.4 ± 0.3  -  Placebo  (n = 452)  (n = 452)  (n = 452)  (n = 452)  NORMALISE  274  Amlodipine  6, 12, 18, 24  17.5 ± 12.0  20.5 ± 15.3  5.0 ± 3.1  0.8 ± 0.6  -  Enalapril  (n = 243)  (n = 263)  (n = 263)  (n = 263)  Placebo  ACTIVATE  408  Pactimibe  3, 6, 12, 18  15.7 ± 10.3  19.1 ± 13.2  4.0 ± 2.5  0.5 ± 0.4  13.3 ± 9.7  Placebo  (n = 394)  (n = 405)  (n = 405)  (n = 405)  (n = 364)a  ILLUSTRATE  910  Atorvastatin  3, 6, 12, 18, 24  11.4 ± 7.6  13.4 ± 11.4  5.5 ± 3.7  0.4 ± 0.3  -  Atorvastatin + Torcetrapib  (n = 143)  (n = 138)  (n = 138)  (n = 138)  STRADIVARIUS  676  Rimonabant  6, 12, 18  15.3 ± 12.5  17.7 ± 14.2  4.6 ± 3.2  0.5 ± 0.6  -  Placebo  (n = 404)  (n = 404)  (n = 413)  (n = 404)  PERISCOPE  360  Pioglitazone  6, 12, 18  16.9 ± 13.0  19.8 ± 14.8  4.6 ± 3.5  0.5 ± 0.5  11.0 ± 8.0  Glimepiride  (n = 334)  (n = 326)  (n = 326)  (n = 326)  (n = 302)  Total  4976      13.7 ± 10.9  16.2 ± 12.9  4.5 ± 3.0  0.4 ± 0.4  10.6 ± 8.0  (n = 3835)  (n = 3860)  (n = 3869)  (n = 3860)  (n = 2347)    n  Treatment arms  Time points available  Variability   (n where 3 or 4 time points)           SD of LDL-C  SD of non-HDL-C  SD of HDL-C  SD of TC/HDL-C  SD of Apo B  REVERSAL  502  Pravastatin  3, 6, 12, 18  13.3 ± 9.3  15.8 ± 12.1  4.1 ± 2.5  0.5 ± 0.4  11.8 ± 7.5  Atorvastatin  (n = 500)  (n = 500)  (n = 500)  (n = 500)  (n = 500)  ASTEROID  349  Rosuvastatin  3, 12, 24  10.5 ± 10.9  12.9 ± 11.9  4.6 ± 3.9  0.3 ± 0.3  10.5 ± 10.1  (n = 338)  (n = 345)  (n = 345)  (n = 345)  (n = 161)  SATURN  1039  Atorvastatin  6, 12, 18, 24  11.1 ± 9.4  13.3 ± 10.6  4.6 ± 2.7  0.3 ± 0.3  8.9 ± 6.5  Rosuvastatin  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1027)  (n = 1020)  AQUARIUS  458  Aliskiren  6, 12, 18, 24  15.8 ± 11.5  17.3 ± 12.7  4.6 ± 2.9  0.4 ± 0.3  -  Placebo  (n = 452)  (n = 452)  (n = 452)  (n = 452)  NORMALISE  274  Amlodipine  6, 12, 18, 24  17.5 ± 12.0  20.5 ± 15.3  5.0 ± 3.1  0.8 ± 0.6  -  Enalapril  (n = 243)  (n = 263)  (n = 263)  (n = 263)  Placebo  ACTIVATE  408  Pactimibe  3, 6, 12, 18  15.7 ± 10.3  19.1 ± 13.2  4.0 ± 2.5  0.5 ± 0.4  13.3 ± 9.7  Placebo  (n = 394)  (n = 405)  (n = 405)  (n = 405)  (n = 364)a  ILLUSTRATE  910  Atorvastatin  3, 6, 12, 18, 24  11.4 ± 7.6  13.4 ± 11.4  5.5 ± 3.7  0.4 ± 0.3  -  Atorvastatin + Torcetrapib  (n = 143)  (n = 138)  (n = 138)  (n = 138)  STRADIVARIUS  676  Rimonabant  6, 12, 18  15.3 ± 12.5  17.7 ± 14.2  4.6 ± 3.2  0.5 ± 0.6  -  Placebo  (n = 404)  (n = 404)  (n = 413)  (n = 404)  PERISCOPE  360  Pioglitazone  6, 12, 18  16.9 ± 13.0  19.8 ± 14.8  4.6 ± 3.5  0.5 ± 0.5  11.0 ± 8.0  Glimepiride  (n = 334)  (n = 326)  (n = 326)  (n = 326)  (n = 302)  Total  4976      13.7 ± 10.9  16.2 ± 12.9  4.5 ± 3.0  0.4 ± 0.4  10.6 ± 8.0  (n = 3835)  (n = 3860)  (n = 3869)  (n = 3860)  (n = 2347)  Apo B, apolipoprotein B cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol. a No 3-month data available for Apo B. Table 4 describes, in separate models, the relationship of annualized change in PAV with lipoprotein variability and average on-treatment lipoprotein values. The SD of atherogenic lipid measurements were significantly associated with PAV progression [β (95% CI), LDL-C: 0.052 (0.024, 0.079), P < 0.001; non-HDL-C: 0.049 (0.021, 0.078), P < 0.001; TC/HDL-C: 0.064 (0.031, 0.096), P < 0.001; ApoB 0.051 (0.016, 0.086), P = 0.004]. There was no significant association between changes in PAV and HDL-C variability [−0.018 (−0.045, 0.009), P = 0.19]. Table 4 Standardized association of lipid variability and average on-treatment value with annualized change in percent atheroma volume   Variability (SD) and ΔPAV   On-treatment value (Avg) and ΔPAV     Standardized  P-value  Standardized  P-value  β (95% CI)  β (95% CI)  LDL-C           Overall population  0.052 (0.024, 0.079)  <0.001  0.119 (0.085, 0.154)  <0.001   Avg On-Tx ≥70 mg/dL  0.039 (0.008, 0.071)  0.015  0.130 (0.079, 0.181)  <0.001   Avg On-Tx <70 mg/dL  0.066 (−0.010, 0.142)  0.09  0.144 (0.032, 0.257)  0.01  Non-HDL-C           Overall population  0.049 (0.021, 0.078)  <0.001  0.141 (0.106, 0.177)  <0.001   Avg On-Tx ≥100 mg/dL  0.021 (−0.013, 0.054)  0.23  0.164 (0.107, 0.221)  <0.001   Avg On-Tx <100 mg/dL  0.071 (0.001, 0.141)  0.046  0.061 (−0.037, 0.159)  0.22  HDL-C           Overall population  −0.018 (−0.045, 0.009)  0.19  −0.075 (−0.119, −0.032)  <0.001   Avg On-Tx ≥ median  −0.013 (−0.044, 0.018)  0.41  −0.081 (−0.138, −0.024)  0.006   Avg On-Tx < median  −0.014 (−0.068, 0.041)  0.62  −0.041 (−0.162, 0.080)  0.50  TC/HDL-C           Overall population  0.064 (0.031, 0.096)  <0.001  0.150 (0.110, 0.190)  <0.001   Avg On-Tx ≥ median  0.033 (−0.005, 0.071)  0.091  0.116 (0.057, 0.176)  <0.001   Avg On-Tx < median  0.075 (−0.002, 0.152)  0.06  0.113 (0.001, 0.224)  0.048  Apo B           Overall population  0.051 (0.016, 0.086)  0.004  0.092 (0.045, 0.138)  <0.001   Avg On-Tx ≥ median  0.031 (−0.015, 0.077)  0.19  0.068 (−0.016, 0.152)  0.11   Avg On-Tx < median  0.046 (−0.012, 0.103)  0.12  0.048 (−0.059, 0.156)  0.38    Variability (SD) and ΔPAV   On-treatment value (Avg) and ΔPAV     Standardized  P-value  Standardized  P-value  β (95% CI)  β (95% CI)  LDL-C           Overall population  0.052 (0.024, 0.079)  <0.001  0.119 (0.085, 0.154)  <0.001   Avg On-Tx ≥70 mg/dL  0.039 (0.008, 0.071)  0.015  0.130 (0.079, 0.181)  <0.001   Avg On-Tx <70 mg/dL  0.066 (−0.010, 0.142)  0.09  0.144 (0.032, 0.257)  0.01  Non-HDL-C           Overall population  0.049 (0.021, 0.078)  <0.001  0.141 (0.106, 0.177)  <0.001   Avg On-Tx ≥100 mg/dL  0.021 (−0.013, 0.054)  0.23  0.164 (0.107, 0.221)  <0.001   Avg On-Tx <100 mg/dL  0.071 (0.001, 0.141)  0.046  0.061 (−0.037, 0.159)  0.22  HDL-C           Overall population  −0.018 (−0.045, 0.009)  0.19  −0.075 (−0.119, −0.032)  <0.001   Avg On-Tx ≥ median  −0.013 (−0.044, 0.018)  0.41  −0.081 (−0.138, −0.024)  0.006   Avg On-Tx < median  −0.014 (−0.068, 0.041)  0.62  −0.041 (−0.162, 0.080)  0.50  TC/HDL-C           Overall population  0.064 (0.031, 0.096)  <0.001  0.150 (0.110, 0.190)  <0.001   Avg On-Tx ≥ median  0.033 (−0.005, 0.071)  0.091  0.116 (0.057, 0.176)  <0.001   Avg On-Tx < median  0.075 (−0.002, 0.152)  0.06  0.113 (0.001, 0.224)  0.048  Apo B           Overall population  0.051 (0.016, 0.086)  0.004  0.092 (0.045, 0.138)  <0.001   Avg On-Tx ≥ median  0.031 (−0.015, 0.077)  0.19  0.068 (−0.016, 0.152)  0.11   Avg On-Tx < median  0.046 (−0.012, 0.103)  0.12  0.048 (−0.059, 0.156)  0.38  Adjusting for baseline PAV, baseline lipid, age, gender, body mass index, diabetes, concomitant statin use, region, number of follow-up lipid values (3 vs. 4), and trial. Apo B, apolipoprotein B cholesterol; Avg, average; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PAV percent atheroma volume; SD, standard deviation; TC, total cholesterol; Tx, treatment. Table 4 Standardized association of lipid variability and average on-treatment value with annualized change in percent atheroma volume   Variability (SD) and ΔPAV   On-treatment value (Avg) and ΔPAV     Standardized  P-value  Standardized  P-value  β (95% CI)  β (95% CI)  LDL-C           Overall population  0.052 (0.024, 0.079)  <0.001  0.119 (0.085, 0.154)  <0.001   Avg On-Tx ≥70 mg/dL  0.039 (0.008, 0.071)  0.015  0.130 (0.079, 0.181)  <0.001   Avg On-Tx <70 mg/dL  0.066 (−0.010, 0.142)  0.09  0.144 (0.032, 0.257)  0.01  Non-HDL-C           Overall population  0.049 (0.021, 0.078)  <0.001  0.141 (0.106, 0.177)  <0.001   Avg On-Tx ≥100 mg/dL  0.021 (−0.013, 0.054)  0.23  0.164 (0.107, 0.221)  <0.001   Avg On-Tx <100 mg/dL  0.071 (0.001, 0.141)  0.046  0.061 (−0.037, 0.159)  0.22  HDL-C           Overall population  −0.018 (−0.045, 0.009)  0.19  −0.075 (−0.119, −0.032)  <0.001   Avg On-Tx ≥ median  −0.013 (−0.044, 0.018)  0.41  −0.081 (−0.138, −0.024)  0.006   Avg On-Tx < median  −0.014 (−0.068, 0.041)  0.62  −0.041 (−0.162, 0.080)  0.50  TC/HDL-C           Overall population  0.064 (0.031, 0.096)  <0.001  0.150 (0.110, 0.190)  <0.001   Avg On-Tx ≥ median  0.033 (−0.005, 0.071)  0.091  0.116 (0.057, 0.176)  <0.001   Avg On-Tx < median  0.075 (−0.002, 0.152)  0.06  0.113 (0.001, 0.224)  0.048  Apo B           Overall population  0.051 (0.016, 0.086)  0.004  0.092 (0.045, 0.138)  <0.001   Avg On-Tx ≥ median  0.031 (−0.015, 0.077)  0.19  0.068 (−0.016, 0.152)  0.11   Avg On-Tx < median  0.046 (−0.012, 0.103)  0.12  0.048 (−0.059, 0.156)  0.38    Variability (SD) and ΔPAV   On-treatment value (Avg) and ΔPAV     Standardized  P-value  Standardized  P-value  β (95% CI)  β (95% CI)  LDL-C           Overall population  0.052 (0.024, 0.079)  <0.001  0.119 (0.085, 0.154)  <0.001   Avg On-Tx ≥70 mg/dL  0.039 (0.008, 0.071)  0.015  0.130 (0.079, 0.181)  <0.001   Avg On-Tx <70 mg/dL  0.066 (−0.010, 0.142)  0.09  0.144 (0.032, 0.257)  0.01  Non-HDL-C           Overall population  0.049 (0.021, 0.078)  <0.001  0.141 (0.106, 0.177)  <0.001   Avg On-Tx ≥100 mg/dL  0.021 (−0.013, 0.054)  0.23  0.164 (0.107, 0.221)  <0.001   Avg On-Tx <100 mg/dL  0.071 (0.001, 0.141)  0.046  0.061 (−0.037, 0.159)  0.22  HDL-C           Overall population  −0.018 (−0.045, 0.009)  0.19  −0.075 (−0.119, −0.032)  <0.001   Avg On-Tx ≥ median  −0.013 (−0.044, 0.018)  0.41  −0.081 (−0.138, −0.024)  0.006   Avg On-Tx < median  −0.014 (−0.068, 0.041)  0.62  −0.041 (−0.162, 0.080)  0.50  TC/HDL-C           Overall population  0.064 (0.031, 0.096)  <0.001  0.150 (0.110, 0.190)  <0.001   Avg On-Tx ≥ median  0.033 (−0.005, 0.071)  0.091  0.116 (0.057, 0.176)  <0.001   Avg On-Tx < median  0.075 (−0.002, 0.152)  0.06  0.113 (0.001, 0.224)  0.048  Apo B           Overall population  0.051 (0.016, 0.086)  0.004  0.092 (0.045, 0.138)  <0.001   Avg On-Tx ≥ median  0.031 (−0.015, 0.077)  0.19  0.068 (−0.016, 0.152)  0.11   Avg On-Tx < median  0.046 (−0.012, 0.103)  0.12  0.048 (−0.059, 0.156)  0.38  Adjusting for baseline PAV, baseline lipid, age, gender, body mass index, diabetes, concomitant statin use, region, number of follow-up lipid values (3 vs. 4), and trial. Apo B, apolipoprotein B cholesterol; Avg, average; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PAV percent atheroma volume; SD, standard deviation; TC, total cholesterol; Tx, treatment. Similarly, the average on-treatment values correlated significantly with PAV progression [LDL-C: 0.119 (0.085, 0.15), P < 0.001; non-HDL-C: 0.14 (0.11, 0.18), P < 0.001; TC/HDL-C: 0.15 (0.11, 0.19), P < 0.001; ApoB 0.09 (0.045, 0.14), P < 0.001]. In this case, average on-treatment HDL-C was significantly associated with PAV regression [−0.075 (−0.12, −0.032), P < 0.001]. Notably, there was not a significant association between LDL-C variability and annualized change in PAV in the population with achieved LDL-C levels <70 mg/dL [0.066 (−0.01, 0.14), P = 0.089]. In the same population however, there was a significant and stronger association between annualized change in PAV and average on-treatment LDL-C [0.14 (0.032, 0.26), P = 0.012]. Figure 1 illustrates the relationship of the binary outcome of PAV progression (or no progression) with lipid particle variability and average on-treatment value. Standard deviation of atherogenic lipid particles significantly associated with PAV progression [OR (95% CI), LDL-C: 1.09 (1.02, 1.17), P = 0.014; non-HDL-C: 1.10 (1.02, 1.18), P = 0.011; TC/HDL-C: 1.14 (1.06, 1.24), P = 0.001; ApoB: 1.13 (1.03, 1.24), P = 0.010]. There was however a more robust association observed between average on-treatment atherogenic lipoproteins and PAV progression [LDL-C: 1.27 (1.17, 1.39), P < 0.001; non-HDL-C: 1.32 (1.21, 1.45), P < 0.001; TC/HDL-C: 1.31 (1.19, 1.45), P < 0.001; ApoB: 1.20 (1.07, 1.35), P = 0.003]. Variability of HDL-C did not significantly associate with PAV progression [1.00 (0.93, 1.07), P = 0.95], and the relationship between average on-treatment HDL-C and PAV progression was borderline significant [0.88 (0.79, 0.99), P = 0.034]. Figure 1 View largeDownload slide Standardized association of variability and average on-treatment cholesterol with coronary atheroma progression. *Adjusting for baseline percent atheroma volume, lipid, age, sex, body mass index, diabetes, concomitant statin use, region, number of follow-up lipid values, and trial. BMI, body mass index; CI, confidence interval; OR, odds ratio; PAV, percent atheroma volume. Figure 1 View largeDownload slide Standardized association of variability and average on-treatment cholesterol with coronary atheroma progression. *Adjusting for baseline percent atheroma volume, lipid, age, sex, body mass index, diabetes, concomitant statin use, region, number of follow-up lipid values, and trial. BMI, body mass index; CI, confidence interval; OR, odds ratio; PAV, percent atheroma volume. Figure 2 illustrates the KM curves assessing MACE among patients stratified across quartiles of lipoprotein SD. At 24 months, there were significant stepwise relationships between cumulative MACE and increasing quartiles of atherogenic lipoprotein SD (KM estimates for quartiles 1–4, respectively: LDL-C: 5.7 vs. 7.3 vs. 7.7 vs. 10.9%, non-HDL-C: 5.1 vs. 7.0 vs. 9.5 vs. 10.5%, TC/HDL-C: 5.2 vs. 8.3 vs. 8.4 vs. 9.9%, ApoB: 3.9 vs. 6.0 vs. 8.8 vs. 11.4%, all log-rank P < 0.01). There was not a significant difference on incidence of MACE between any pair of SD quartiles of HDL-C (overall P = 0.30). Figure 2 View largeDownload slide Major adverse cardiovascular events among patients stratified across quartiles of lipoprotein variability. ApoB, apolipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation; TC, total cholesterol. Figure 2 View largeDownload slide Major adverse cardiovascular events among patients stratified across quartiles of lipoprotein variability. ApoB, apolipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation; TC, total cholesterol. For these analyses, similar results are seen when measuring lipoprotein variability using average successive variability, as presented in Supplementary material online, Tables SI and SII. Discussion In this posthoc patient-level analysis of nine clinical trials utilizing serial coronary IVUS, we demonstrate that greater visit-to-visit variability in atherogenic lipoprotein levels is independently associated with coronary atheroma progression and adverse cardiovascular outcomes. Our results confirm prior work demonstrating cholesterol variability as a predictor of cardiovascular events1–3 and further extend these findings across a range of atherogenic lipoprotein measurements including LDL-C, non-HDL-C, TC/HDL-C, and ApoB. The present analysis is the first to demonstrate that atherogenic lipoprotein variability is directly associated with a proatherosclerotic process, thereby providing a plausible mechanism linking this variability with the increased risk of cardiovascular events. The association however, between achieved lipoproteins and changes in coronary atheroma volume was comparatively stronger, highlighting the importance of aggressively lowering atherogenic lipoproteins in at-risk individuals. Recent analysis of the treating to new targets (TNT) trial demonstrated that LDL-C visit-to-visit variability predicts cardiovascular events independent of achieved LDL-C levels.1 These findings raised the possibility that LDL-C variability may represent a phenomenon contributing to residual risk among those with coronary artery disease already receiving optimal medical therapy. Subsequent analysis from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial demonstrated that higher visit-to-visit LDL-C variability was associated with lower neurocognitive performance, lower cerebral blood flow, and greater white matter hyperintensity on brain magnetic resonance imaging.2 Additionally, cholesterol variability was shown to associate with all-cause mortality, MI, and stroke in a large cohort broadly representative of the general Korean population.3 The association with cholesterol variability and cardiovascular outcomes now seems established; however, in order to target future interventions it is important to delineate pathophysiologic characteristics linking laboratory findings and clinical outcomes. Although the possibility for unmeasured confounders cannot be excluded in the present analysis, the clear association between atherogenic lipoprotein variability and plaque progression suggests a cholesterol-mediated proatherosclerotic effect as compared with a more general homeostatic imbalance affecting cardiovascular risk through other pathophysiologic mechanisms. The biological mechanisms underlying lipoprotein variability and the association with atheroma progression warrants further investigation. Multivariable modelling in the current analysis considered a number of potentially important factors including glucose control, BMI, concomitant statin use, and baseline lipid measurements. It is widely recognized that statins promote atheroma regression likely through reductions of the lipid, inflammatory, and necrotic plaque components.6 One hypothesis is that lipoprotein variability hinders lipid efflux from atheroma resulting in ongoing plaque volume progression (attenuating the effects of risk-modifying therapies); a process that significantly associates with incident cardiovascular events.16–19 Therapeutic means of lowering atherosclerotic and cardiovascular risk is fundamentally based on LDL-C reduction. However, among those who achieve low LDL-C levels, additional lipoproteins including TG, non-HDL-C, and Apo B contribute to residual risk. Furthermore, TC/HDL-C more accurately identifies atheroma progression and may better reflect atherogenic lipid particles, especially when LDL-C, Apo B, and non-HDL-C levels are discordant.20 The current analysis supports that variability of all lipoproteins is associated with plaque progression, and it is important to note the absence of association with HDL-C variability which is consistent with lack of benefit seen drug trials targeting HDL-C. The results of this analysis support the role of variability not only with LDL-C but also other atherogenic lipoproteins, and further research is required to better understand the mechanism underscoring these findings. The results of this analysis may have implications when considering the management of patients at risk for atherosclerotic heart disease. Among patients receiving statin therapy, current guidelines recommend periodic monitoring of lipid levels to assess adherence and therapeutic response.21–23 The present analysis suggests that serial lipid level monitoring is important to identify variability, in addition to statin hyporesponders, in order to intensify broader preventive therapy in higher-risk individuals.24 Also, intermittent statin dosing is an increasingly employed treatment strategy in statin intolerant patients based on effective LDL-C lowering in observational studies,25 yet these patients have substantially higher rates of cardiovascular events than those without statin intolerance.26 On-treatment atherogenic lipoprotein levels were found to harbour a more robust association with changes in atheroma volume, highlighting the well-established importance of aggressively lowering lipoprotein levels. These findings also lend further support to the ‘lower is better’ notion of LDL-C lowering, recently illustrated by the complementary findings of the GLAGOV and FOURIER randomized trials involving aggressive LDL-C with evolocumab.27,28 However, the present analysis also suggests that stability, in addition to reduction, may be an important consideration among statin intolerant patients who often require multiple medication regimen changes. Further studies are needed to assess the relationship between medication dosing, lipid reduction, lipid stability, and cardiovascular events. Several caveats of the current analysis warrant further consideration. This analysis is limited to patients enrolled in clinical trials with established coronary artery disease with an indication for coronary angiography and may not be applicable to those without documented atherosclerotic heart disease. Despite a rigorous statistical approach and relatively uniform inclusion/exclusion criteria in each trial, unmeasured confounding biasing the results cannot be excluded. Lipid measurements used in the variability assessment were obtained throughout the trial and therefore may introduce bias among those with non-fatal MACE prior to the end of follow-up. This limits the interpretation of the relationship between lipoprotein variability and MACE, and it is important emphasize that these findings represent an association and are thus considered hypothesis generating. On the other hand, the present data are unique in analysing a variety of lipoprotein variables across multiple clinical trials using appropriate statistical means to account for both confounders and the range of trialled therapies included in this analysis. Detailed pill counts were not a routine part of the serial IVUS trials included in this analysis; however, compliance rates were shown to be systematically >90% across these trials, thereby minimizing the issue of medication non-compliance significantly influencing the results. In conclusion, in patients with coronary artery disease receiving established medical therapies, greater visit-to-visit variability in atherogenic lipoprotein levels significantly associates with coronary atheroma progression and adverse clinical outcomes. These observations, coupled with stronger associations between achieved lipoprotein levels and plaque progression–regression, highlight the dual importance of not only aggressively lowering atherogenic lipoproteins levels but also achieving stable reductions. Further research is required to unravel mechanisms promoting lipoprotein variability, including its therapeutic implications. 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European Heart JournalOxford University Press

Published: Apr 21, 2018

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