Which CVS risk reduction strategy fits better to carotid US findings?

Which CVS risk reduction strategy fits better to carotid US findings? Dougalis A, Soulaidopoulos S, Cholongitas E, Chalevas P, Vettas Ch, Doumtsis P, Vaitsi K, Diavasti M, Mandala E, Garyfallos A 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, GREECE

Background-1: Carotid US imaging Carotid US imaging: a non-invasive tool to track atherosclerotic changes in arterial walls. IMT (intima-media thickness): predictive of future CVS events. Meta-analysis 1, 8 trials, 37197 patients followed for 5.5years (mean): relative risk for every 0.1mm IMT MI 1.15, Stroke 1.18. Change of IMT: not predictive of CVS events 2,3. Perhaps due to methodological problems related to intra- and interobserver variability. It seems unlikely that progression of carotid atherosclerosis would not predict outcome. Use of IMT change as a surrogate endpoint measure of drug efficacy is debated. 1. Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007; 115:459-467. 2. Costanzo P, et al. "Does carotid intima-media thickness regression predict reduction of cardiovascular events? A meta-analysis of 41 randomized trials". J Am Coll Cardiol 56 (24): 2006 20. 3. Lorenz MW et al. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a metaanalysis of individual participant data". Lancet 379 (9831): 2053 62.

Backround-2: Guidelines concerning IMT measurement and plaques screening European: SCORE (ESC/EAS) 2012 1 : Subjects with 10y risk (fatal CVS disease) 1-5% (moderate risk), for further risk assessment (IIa, B). SCORE (ESC/ESH) 2013 2 : Hypertensive subjects at moderate risk, because IMT>0.9mm or plaques is considered target organ damage (so are pulse pressure 60 mmhg, carotid-femoral pulse wave velocity > 10 m/s and ankle-brachial index < 0.9). There is evidence that asymptomatic target organ damage predicts cardiovascular death independently of SCORE (IIa, B). American: ACC/AHA 2013 3 : IMT measurement is not recommended for routine measurement in clinical practice for risk assessment for a first atherosclerotic cardiovascular disease event. Serial studies of IMT to assess progression or regression in individual patients are not recommended. ASE (American Society of Echography) 2012 4 : Patients at intermediate risk, to refine risk assessment: 6-20% 10-year risk of MI or CVD death, without established CAD or its equivalents. Those with a family history of premature CVD in a first-degree relative. Individuals <60y with severe abnormalities in a single risk factor who otherwise would not be candidates for pharmacotherapy. Females <60y with 2 risk factors. 1. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). European Heart Journal (2012) 33, 1635 1701. 2. 2013 ESH/ESC Guidelines for the management of arterial hypertension. European Heart Journal 2013 34;2159 2219. 3. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk. J Am Coll Cardiol. 2014; 63(25 Pt B):2935-59. 4. ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults. J Am Coll Cardiol. 2010;56:e50 e103.

IMT normal values Age- and sex-dependent. Significant steady increase in IMT with advancing age in all carotid segments 1-3. Significantly higher IMT values in men than in women. The relationship of IMT with CVS risk is continuous, so, dichotomizing this parameter (i.e. determining a threshold IMT value) would be incorrect. ESH/ESC hypertension guidelines (2013): IMT > 0.9 mm re-confirmed 4 as a marker of asymptomatic organ damage, although it has been proven that in middle-aged and elderly patients the threshold values indicating high cardiovascular risk are higher. The American Society of Echography (ASE) Task force recommends that: IMT 75th percentile is considered high and indicative of increased cardiovascular risk. Values from the 25th to the 75th percentile are considered average and indicative of unchanged cardiovascular risk. Values 25th percentile are considered low and indicate lower than the expected cardiovascular risk. More conservative cut-off suggestions: IMT values age-adjusted 97.5th percentile to be defined as abnormal (and predictive of increased vascular risk). In a large cross-sectional study the association of CCA-IMT with vascular risk has been found to be present only for values falling in the highest quintile of the population values. NORMAL IMT VALUES/PERCENTILE GENDER/AGE P25 P50 P75 MALE 41-50 0.46 0.50 0.57 MALE>50 0.46 0.52 0.62 FEMALE 41-50 0.44 0.48 0.53 FEMALE >50 0.50 0.54 0.59 1. Age-adjusted reference limits for carotid intima-media thickness, Tosetto A et al, J Thromb Haemost. 2005; 3:1224 1230. 2. Prospective Data From the Carotid Atherosclerosis Progression Study (CAPS), Lorenz MW et al, Stroke 2006; 37: 87-92. 3. Country-based reference values and impact of cardiovascular risk factors on carotid intima-media thickness in a French population: the 'Paroi Artérielle et Risque Cardio-Vasculaire' (PARC) Study, Touboul PJ et al, Cerebrovasc Dis. 2009; 27(4):361-7. 4. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group, O'Leary DH,et al, N Engl J Med 1999;340:14-22.

Background-3: CVS Risk evaluation and Lipid Lowering Guidelines (primary prevention) ESC/EAS: SCORE system. 10y risk of fatal CVD. Main risk factors: age, sex, smoking, SBP, TC. Additional risk factors (risk higher than indicated in the chart): DM2, obesity, sedentary lifestyle, family history of premature CVD, HDL, TG, Fib, ApoB, Lp(a), CRP, preclinical atherosclerosis (US plaques), CKD (GFR<60ml/min/1.73m 2 ). LDL-target: Moderate risk (1-4%) <115mg/dl, high risk (5-9% or alternatives) <100mg/dl, very high risk (10% or alternatives) <70mg/dl. AHA/ACC: ASCVD risk. 10y risk of CHD death, non fatal MI, fatal or non fatal stroke. Main risk factors: age, sex, race, smoking, SBP, treatment for BP, TC, HDL, DM. Statin Intensity: LDL (70-189mg/dl, 190mg/dl), ASCVD risk (<7,5%, 7,5%), DM. Low, moderate or high intensity statin therapy.

AIM To assess carotid US findings together with 2 different approaches of CVS risk estimation and lipid-lowering therapy: ESC/EAS policy (LDL-target, treat-to-target ). AHA/ACC policy (Statin intensity, fire-and-forget ).

METHODS Subjects Carotid US SCORE risk ASCVD risk

Subjects 71 primary prevention subjects, aged 40-75y, 31 40. Age: 56.5±9.6 years. BMI: 28.48±4.41 kg/m 2. Smoking: 34/71(47.8%). AH: 30/71(42.2%). DM: 8/71(11.2%). Family history of early CVD: 22/71(30.9%). SBP: 127.05±16.8mmHg. TC: 261.39±46.2mg/dl. TG: 170.14±86.2mg/dl. HDL: 54.72±15.8mg/dl. LDL: 171.04±42.4mg/dl.

Carotid US Observation standards 1 : Locations: CCA, bifurcation, bulb, ICA, ECA. IMT measurement along a segment of the artery >10mm, free of atherosclerotic plaque with clearly defined lumen-intima and mediaadventitia interfaces. The far wall of the common carotid artery was preferred. IMT measured in triplicate. Maximum IMT was taken into account. Carotid findings grading: Grade 0: IMT 0.49mm. Grade 1: 0.5-0,99mm. Grade 2: 1mm. Grade 3: Plaques with measurable stenosis (<70%). 1. E-journal of the ESC Council for Cardiology Practice, Vol. 13, N 21-05 May 2015.

SCORE Risk Risk calculation according to: Main risk factors: Age, Gender, Smoking, SBP, TC. Additional risk factors (risk higher than indicated in the chart): DM2, obesity, sedentary lifestyle, family history of premature CVD, HDL, TG, Fib, ApoB, Lp(a), CRP, preclinical atherosclerosis (US plaques), CKD (GFR<60ml/min/1.73m 2 ). LDL-target assignment, according to risk. Moderate risk (1-4%) <115mg/dl, high risk (5-9% or alternatives) <100mg/dl, very high risk (10% or alternatives) <70mg/dl.

ASCVD Risk Risk calculation, according to: Age, gender, race, smoking, SBP, treatment for BP, TC, HDL, DM. Statin intensity assignment, according to: LDL (70-189mg/dl, 190mg/dl), ASCVD risk (<7,5%, 7,5%), DM. Low, moderate or high intensity statin therapy.

DATA ANALYSIS CHI-square test for independence.

RESULTS Carotid US findings and treatment strategy assignment: which fits best?

GRADES OF CAROTID US FINDINGS AND CVS RISK FACTORS GRADE 0 (IMT 0.49mm) N:6 GRADE 1 (IMT 0.5-0.9mm) N:27 GRADE 2 (IMT 1mm) N:12 GRADE 3 (PLAQUES) N:26 AGE 48.5±6.8 53.1±9.8 55.3±8.1 62.4±7.4 GENDER 2 /4 11 /16 4 /8 14 /12 BMI 32.01±6.1 28±4.3 28.5±4.1 28.2±4.1 SMOKING 1/6 (26%) 9/27 (33%) 9/12 (75%) 10/26 (38%) SBP 121.7±9.8 131.32±2.6 132.3±26.6 141.7±18.7 TC 245.2±39.8 271.3±40.9 257.3±48.2 256.7±52 TG 178±56 158±67 176±68 179±115 HDL 47.8±9.2 58.4±20 49.2±14.3 55±11.7 LDL 158.8±37.6 177±38 174.2±5.1 165.4±48.1 LP(a)>30mg/dl 0/6 4/27 (15%) 1/12 (8%) 2/26 (7.7%) DM 0/6 1/27 (4%) 2/12 (16%) 5/26 (19%) FAMILY HISTORY EARLY CVD 2/6 (33%) 11/27 (41%) 5/12 (40%) 5/26 (19%)

SCORE-BASED vs TRIPLEX-BASED LDL-TARGET IMT>0,5mm or plaques LDL-target<100mg/dl. N:71 GRADE 0 (IMT 0.49mm) N:6 GRADE 1 (IMT 0.5-0.9mm) N:27 GRADE 2 (IMT 1mm) N:12 GRADE 3 (PLAQUES) N:26 LDL-target (mg/dl) >100 right <100 wrong <100 right >100 wrong <100 right >100 wrong <100 right >100 wrong TRIPLEX 6/6 0/6 27/27 0/27 12/12 0/12 26/26 0/26 SCORE 6/6 0/6 6/27 (23%) 21/27 (77%) 7/12 (58.4%) 5/12 (41.6%) 14/26 (53.9%) 12/26 (46.1%) p: NS 0.0003 0.062 0.035 A significant percentage of patients with Grade-1, -2 or -3 findings were assigned to LDLtargets less aggressive than expected (Grade1 77%, p=0.0003, Grade2 41.6%, p=0.062, Grade3 46.1%, p=0.035).

GRADES OF CAROTID US: COMPARING No OF PATIENTS ASSIGNED TO EITHER LDL-TARGET OR STATIN INTENSITY CATEGORIES US FINDINGS GRADE LDL-target <115 Statin LOW LDL-TARGET/STATIN INTENSITY CATEGORIES p LDL-target <100 Statin MEDIUM p LDL-target <70 Statin HIGH p 0 (N=6) 6/6 (100%) 4/6 (66%) NS 0/6 2/6 (33%) NS 0/6 0/6 NS 1 (N=27) 21/27 (77.5%) 10/27 (37%) 0.005 5/27 (18.5%) 13/27 (48.1%) 0.04 1/27 (4%) 4/27 (14.9%) NS 2 (N=12) 5/12 (41.6%) 3/12 (25%) NS 6/12 (50%) 8/12 (66.6%) NS 1/12 (8.4%) 1/12 (8.4%) NS 3 (N=26) 12/26 (46.1%) 4/26 (15.4%) 0.01 9/26 (34.7%) 11/26 (42.3%) NS 5/26 (19.2%) 11/26 (42.3%) NS A significantly higher percentage of patients with either Grade 1 or Grade 3 carotid US findings was assigned to a less aggressive LDL-target, compared to the percentage assigned to a low-power statin. AHA/ACC strategy seemed to correspond to worsening carotid US findings better than ESC strategy.

CONCLUSIONS Carotid US imaging provides an extra tool for CVS risk evaluation. According to carotid US findings, AHA/ACC lipid lowering strategy seems to provide a better risk evaluation and lowering.

DISCUSSION ESC risk evaluation/therapeutic strategy: Based on less and more simple risk factors. Contribution of additional risk factors unclear. Level of contribution of each individual factor. Cumulative effect. Statin therapy less aggressive, in some cases it has to be based on the physician s judgment. AHA/ACC risk evaluation/therapeutic strategy: Based on more risk factors. Statin therapy more aggressive, based basically on standard criteria. Given the predictive importance of carotid US, it seems reasonable to use it, especially when it is difficult to choose a treatment strategy.

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