Central pressures and prediction of cardiovascular events in erectile dysfunction patients

Transcription

1 Central pressures and prediction of cardiovascular events in erectile dysfunction patients N. Ioakeimidis, K. Rokkas, A. Angelis, Z. Kratiras, M. Abdelrasoul, C. Georgakopoulos, D. Terentes-Printzios, C Fassoulakis, C. Vlachopoulos, D. Tousoulis Cardiovascular Diseases and Sexual Health Unit, 1 st Dep of Cardiology, Athens Medical School Department of Urology, Hippokration Hospital

2 Background Central (aortic) blood pressures (BP) more accurately reflect loading conditions of vital organs and thus, should better related to target organ damage and cardiovascular events than peripheral pressures. The purpose of the present study was to investigate whether central haemodynamics predict major adverse cardiovascular events (MACEs) in patients with erectile dysfunction (ED) beyond traditional risk factors..

3 Central pressures and Augmentation index Central pressures do not correspond to brachial pressures due to pressure pulse amplification of a varying degree when moving from the aorta to the periphery. Central (aortic, carotid) pressures are pathophysiologically more relevant than peripheral pressures for the pathogenesis of cardiovascular disease.

4 Study Protocol 398 ED pts (mean age 56 yrs) Assessment of ED Augmentation Index was defined as augmented pressure (AP=maximum systolic pressure - pressure at the inflection point) divided by pulse pressure and expressed as percentage. Higher values of AIx indicate increased arterial stiffening and wave reflections and vice-versa.

5 Study Protocol Primary end-points Information on major adverse cardiac events (MACEs) up to May 2015 was obtained by visits to our unit, phone interview, or mail. Each subject or a family member completed the questionnaire on MACEs, current medication, and health status. MACEs analyzed as the end points of this study included cardiovascular death, CAD, stroke, and peripheral arterial disease. All MACEs included in analysis were validated by research doctors who were unaware of the patient s arterial stiffness tests using source data, including death certificates, hospital record forms, and interview.

6 Statistical analysis Population analysis We assessed differences in normal variables by the Student t-test and differences in non-normal variables by the Mann- Whitney U test. The Pearson chi-square test was used for frequency comparison. The ANCOVA (analysis of covariance) was used to determine whether there are any significant differences between the central pressure means of two or more independent groups (specifically, the adjusted means). Outcome and prognostic impact of central haemodynamics Free of MACE survival among central P and AIx tertiles was estimated by Kaplan-Meier curves and compared by the Mantel log-rank test. The primary analyses used the unadjusted Cox proportional hazards estimates to evaluate the risk ratios of CV risk factors. The primary analyses used the unadjusted Cox proportional hazards estimates to evaluate the risk ratios of (a) CV risk factors, such as age, hypercholesterolemia, obesity, smoking, (b) BP level (systolic, diastolic, pulse pressure), and (c) biological variables such as fasting glucose, total cholesterol, triglycerides, HDL TT and hscrp. Since 10 events per covariate is recommended, a series of multivariate Cox regression models with no more than 4 variables at a time were applied to determine the independent effect of central pressure parameters on MACE. The Cox models were adjusted for (i) central systolic and pulse pressure, AIx, AP, (ii) the two most important covariates according to univariate Cox analysis (age and systolic blood pressure) and (iii) each of the other variables at a time in rotation. The robustness of the estimated hazard ratios was evaluated using bootstrap re-sampling method of 1000 datasets. A bias of the estimate less than 0.01 was considered adequate for the performance of the calculated hazard ratio. Incremental predictive usefulness of central haemodynamics As we had 6.5 years of follow-up in our study, for the reclassification analysis we did not use standard risk categories based on Framingham Risk Score (FRS). Instead, we computed the predicted risk for all patients using a Cox regression model that included only the standard risk factors used for calculation of FRS (global CV risk) (age, systolic BP, cholesterol, HDL-cholesterol, smoking). To better identify a group that the aortic PP and AIx reclassifies patients in a considerable percentage we defined cut-off points for risk groups according to the quartiles of the predicted risk in patients who experienced an event during the 4.9-year follow-up. Then, we constructed three groups of risk. We cross-classified groups of risk based on a model that included standard risk factors against groups of risk based on a model where central aortic PP and AIx were added. Cross-classification was evaluated separately in patients who did or did not experience an event. We then calculated the net reclassification index (NRI), which quantifies the ability of the investigated parameters to predict risk when added to the classical risk factors. The NRI was calculated as the sum of i) the difference in proportions of patients reclassified into a higher risk group minus the proportion reclassified into a lower risk group among men who developed events, plus ii) the difference in the proportion of patients reclassified into a lower risk category minus the proportion reclassified into a higher risk group among men who did not develop events. The significance of the net reclassification improvement was assessed with an asymptotic test as described by Pencina et al.

7 Results The mean follow-up time was 6.5 years (range 1-11), during which 29 (7.2%) subjects developed MACE (24 nonfatal, 5 fatal). Of those with CAD events (n=20), 2 were fatal, 4 were myocardial infarction with survival beyond one day and 14 were documented angina pectoris or coronary revascularization. Other MACE events were cerebrovascular events (n=6), and new onset of peripheral arterial disease (n=3, 1 fatal).

8 Results Table 1. Baseline clinical characteristics of patients with a MACE and subjects without MACE MACE No MACE *P value (n=29) (n=369) Age (years) 61±6 55±10 <0.001 BMI (Kgr/m 2 ) 27.8± ± Total cholesterol, mg/dl 209±34 207± HDL cholesterol, mg/dl 44±8 45± Triglycerides, mg/dl 111 (75-136) 109 (80-131) 0.98 Glucose, mg/dl 107 (86 117) 105 (84 115) 0.54 hscrp, mg/l 1.9 ( ) 1.7 ( ) 0.43 Total testosterone, ng/ml 4.0 ± ±1.2 <0.05 Hypertension, n (%) 24 (83) 170 (48) <0.001 Hypercholesterolemia, n (%) 16 (55) 212(60) 0.39 Diabetes, n (%) 6 (21) 61(17) 0.37 Smoking, n (%) 16 (55) 187 (53) 0.48 Drug Therapy, n (%) Antihypertenive therapy 20 (69) 156 (42) Statins 11 (38) 114 (31) 0.47 IIEF ±3 13.2± PSV (cm/s) 29±10 33± BMI: body-mass index; BP: blood pressure; CV: cardiovascular; ED: erectile dysfunction; FRS: Framingham Risk Score; HDL: high density lipoprotein; hscrp: high sensitivity C-reactive protein; MACE: major adverce cardiovascular events; PSV: peak systolic velocity Categorical variables are presented as absolute (relative) frequencies; continuous variables, as mean ±SD or median (interquartile range) PSV was measured in 278 ED patietns (25 with MACE and 253 w/o MACE)

9 Results Table 2. Peripheral and Central BP characteristics of patients with a MACE and subjects without MACE MACE No MACE *P value (n=29) (n=369) Heart rate (bpm) 69±8 70± Brachial Systolic BP, mmhg 140±17 131± Brachial Diastolic BP, mmhg 84±7 82± Brachial Pulse Pressure, mmhg 56±13 49±13 <0.001 Mean Pressure, mmhg 103±10 100± Central Systolic BP, mmhg 130±16 121± Central Diastolic BP, mmhg 84±7 83± Central Pulse Pressure, mmhg 56±13 48±13 <0.001 Augmentation Index (%) 30±10 24±10 <0.001 Augmented Pressure (mm Hg) 17±10 10±4 <0.001 BP: blood pressure; MACE: major adverce cardiovascular events; Continuous variables, as mean ±SD *P value: refers to differences between patients with a MACE and subjects without MACE

10 Augmentation Index Results Augmented pressure Longrank=10.06 P=0.002 Long-rank=10.54 P<0.001 Aortic Pulse Pressure Aortic Systolic Pressure Long-rank=9.75 P=0.005 Long-rank=4.99 P=0.08

11 Table 1: MACE by tertiles of AIx 1 st tertile <20% 2nd tertile 20-29% 3rd tertile >29% HR (95% CI) for MACE Unadjusted 1 (REF) 1.52 ( ) 3.69 ( ) Adjusted for age, SP, chol, smoking 1 (REF) 1.16 ( ) 2.50 ( ) P<0.01, P<0.05 for 3 rd terile vs 1 st tertile Table 2 : MACE by tertiles of Ao Systolic pressure 1 st tertile <116 mmhg 2nd tertile mmhg 3rd tertile >127 mmhg HR (95% CI) for MACE Unadjusted 1 (REF) 1.14 ( ) 2.55 ( ) Adjusted for age, SP, chol, smoking 1 (REF) 1.10 ( ) 2.11 ( ) P<0.05 for 3 rd terile vs 1 st tertile Table 3 : MACE by tertiles of Ao Pulse pressure 1 st tertile <34 mmhg 2nd tertile mmhg 3rd tertile >42 mmhg HR (95% CI) for MACE Unadjusted 1 (REF) 1.49 ( ) 4.04 ( ) Adjusted for age, SP, chol, smoking 1 (REF) 1.21 ( ) 2.67 ( ) P<0.01, P<0.05 for 3 rd terile vs 1 st tertile Table 4 : MACE by tertiles of Brachial Pulse pressure 1 st tertile <45 mmhg 2nd tertile mmhg 3rd tertile >55 mmhg HR (95% CI) for MACE Unadjusted 1 (REF) 1.40 ( ) 3.55 ( ) Adjusted for age, SP, chol, smoking 1 (REF) 1.18 ( ) 2.05 ( ) Total Total Total Total P<0.01, P<0.05 for 3 rd terile vs 1 st tertile

12 Table. Predicted risk for a major cardiovascular event (MACE) before and after reclassification with AIx in ED patients who did (A) or did not (B) experience a MACE Model w/o AIx (A) MACE Model with AIx <4.5 % % >8 % Total <4.5 % 10 (34.4%) 2 (6.9%) 0 (0%) 12 (41.3%) % 3 (10.4%)* 2 (6.9%) 3 (10.4%) 8 (27.7%) >8 % 0 (0%)* 2 (6.9%)* 7 (24.1%) 9 (31.0%) Total 13 (44.8%) 6 (20.7%) 10 (34.5%) 29 (100%) Model w/o TT (B) no MACE Model with AIx <4.5 % % >8 % Total <4.5 % 92 (28.3%) 14 (4.3%)* 0 (0%)* 106 (32.6%) % 41 (12.7%) 31 (9.5%) 38 (11.7%)* 110 (33.9%) >8 % 0 (0%) 19 (5.8%) 90 (27.7%) 109 (33.5%) Total 133 (40.0%) 64 (19.6%) 128 (39.4%) 325 (100%) no reclasssification; correct reclassification; *wrong reclassification Values on each row to the right of the value with an asterisk were upwardly classified, and those to the left were downwardly classified by the model that included TT Despite this finding, high aortic P and AIx did not significantly improve the prediction of MACE incidence beyond traditional risk factors (clinical net reclassification index: 6.4%, P=0.35).

13 Conclusions * Our results show that higher aortic BP and AIx are associated with increased risk for a MACE in ED patients without known CVD. * Considering the adverse prognostic role of central haemodynamics on CV outcomes, the present findings may explain part of the increased CV risk associated with ED.