Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis

Peripheral Vessels Unit, 1st Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece (CV, KA, CS); St. Vincent's Clinic, Victor Chang Cardiac Research Institute and University of New South Wales, Sydney, Australia (MFOR); Diagnosis and Therapeutic Center, Hopital Hotel-Dieu, Paris, France (MES)

Dear Editor, We thank Protogerou et al [1] for their interest in our paper [2]. The aim of our analysis was to include all published (till that date) papers and potential methodological limitations were not an exclusion criterion. However, the study of Dart et al. [3] has been criticized on the basis of methodological flaws [4,5] that may account for the unexpected negative pulse pressure amplification [6]. Protogerou et al make a justified argument on raising the issue of an analysis without this respective study [3]. Accordingly, a new meta-analysis we performed excluding this study [3] yielded the following results: Random effects model showed that relative risk (RR) of total cardiovascular (CV) events was 1.158 (95% CI 1.081-1.240) for an increase of central PP by 10mmHg, corresponding to a risk increase of 15.8%. Importantly, central pulse pressure was associated with a higher RR of clinical events than brachial pulse pressure [1.338 (95% CI 1.236-1.448) vs. 1.178 (95% CI 1.091-1.272), P=0.017). We believe that these insightful new data add to the final verdict [1].

References:

1. Protogerou AD, Papadogiannis D, Blacher J. "Central pulse pressure versus peripheral pulse pressure": case still open? Eur Heart J 2010. [e- letter]

2. Vlachopoulos C, Aznaouridis K, O'Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J 2010. [in press]

3. Dart AM, Gatzka CD, Kingwell BA, Willson K, Cameron JD, Liang YL, Berry KL, Wing LMH, Reid CM, Ryan P, Beilin LJ, Jennings GLR, Johnston CI, McNeil JJ, MacDonald GJ, Morgan TO, West MJ. Brachial blood pressure but not carotid arterial waveforms predict cardiovascular events in elderly female hypertensives. Hypertension 2006;47:785-790.

4. O'Rourke MF, Nichols WW, Safar ME. Effects of Angiotensin- Converting Enzyme Inhibitors on Central Blood Pressure. Hypertension 2007;50:e63; author reply e64.

5. O'Rourke MF, Adji A. Clinical use of applanation tonometry: hope remains in Pandora's box. J Hypertens 2010;28:229-33.

6. Avolio, A., L. Van Bortel, P. Boutouyrie, D.W. Cockcroft, C.M. McEniery, A.D. Protogerou, M.J. Roman, M.E. Safar, P. Segers, and H. Smulyan. The role of pulse pressure amplification in arterial hypertension: Experts' opinion and review of the data. Hypertension 2009; 54:375-383.

Conflict of Interest:

None declared

In their recent paper, Vlachopoulos et al (1) presented the results of their meta-analysis of 11 longitudinal studies that employed measures of central haemodynamics as predictors of cardiovascular events, including a total of 5,648 subjects followed for a mean period of 45 months. The authors show that augmentation index (AIx) predicts clinical events independently of peripheral pressures. These important and opportune results strongly support the value of AIx as an informative hemodynamic index for cardiovascular risk stratification. Since the preparation of their manuscript, new studies have been published assessing central pressures and AIx as predictors of cardiovascular events. A recent study showed that among 2,232 Framingham Study participants followed during a median period of 7.8 years, carotid AIx did not independently predict major cardiovascular events (standardized hazard ratio: 0.91; 95%CI: 0.77- 1.07).(2) An updated report by Weber et al (3) demonstrated that in their cohort of 520 male patients undergoing coronary angiography followed for a mean period of 49 months, AIx was predictive of a composite endpoint of all-cause mortality, myocardial infarction, stroke, cardiac, cerebrovascular, and peripheral revascularization after adjustment for age, coronary artery disease severity, mean arterial pressure and brachial pulse pressure (Hazard ratio per 10% increase in AIx=1.15; 95%CI=1.006- 1.316). After further adjustment for various predictors, the hazard ratio per 10% increase was 1.264 (95%CI=1.058-1.509).(3) Finally, the study by Kang-Ling et al (4) showed that among 1,272 participants followed for a median period of 15 years, carotid AIx was predictive of all-cause and cardiovascular mortality only in men, although a trend was observed for women. These new data may impact the effect size estimates obtained by a meta- analysis of available studies. It would be very useful to know how the main results would be affected by including these new studies in the analysis.

References

1. Vlachopoulos C, Aznaouridis K, O'Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J. Epub ahead of print.

2. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, Benjamin EJ. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation; 121(4):505-511.

3. Weber T, O'Rourke M F, Lassnig E, Porodko M, Ammer M, Rammer M, Eber B. Pulse waveform characteristics predict cardiovascular events and mortality in patients undergoing coronary angiography. J Hypertens.

4. Wang KL, Cheng HM, Sung SH, Chuang SY, Li CH, Spurgeon HA, Ting CT, Najjar SS, Lakatta EG, Yin FC, Chou P, Chen CH. Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study. Hypertension; 55(3):799-805.

Conflict of Interest:

None declared

Athanase D. Protogerou, MD, Dimitrios Papadogiannis, MD, Jacques Blacher, MD.

Hypertension Center, 1st Department of Propaedeutic Medicine, Laiko Hospital, Medical School, National & Kapodistrian University of Athens, Greece (ADP, DP) and Paris-Descartes University, Faculty of Medicine, Hotel-Dieu Hospital, AP-HP, Diagnosis Center, Paris, France (JB)

Address for correspondence: A. Protogerou, MD Hypertension Center, 1st Propaedeutic Department of Internal Medicine, Laikon Hospital, National and Kapodistrian University of Athens, 17 Agiou Thoma St., Goudi 11527, Athens, Greece. Tel: 0030 210 6461808 Fax: 0030 210 6461808 e-mail: [email protected]

The study by Vlachopoulos et al. [1] is a robust and remarkable metanalysis on a "hot" and ongoing debate: the case of "central versus peripheral hemodynamics". Augmentation index (AI) was shown to be an independent predictor of clinical events. Central pulse pressure (PP) was marginally non-significantly better than peripheral PP regarding the prediction of clinical outcome [1]. The latter finding merits further discussion.

It is well described by both invasive and non-invasive studies that the pressure wave is amplified (PP amplification), as it travels distally and peripheral PP is higher than central by 30 to 1 mmHg, even in the elderly [2]. A major difficulty while investigating the probable clinical superiority of central over peripheral PP regarding CV risk prediction is the inaccurate assessment of PP amplification by the available non- invasive methods [2]. This is largely related to flaws in the assessment of mean BP used to calibrate the acquired pressure waveform [3]. So far there is no consensus regarding the "gold standard" methodology to assess PP amplification [2][4].

Between the five identified studies fulfilling the criteria and included in the metanalysis comparing central versus peripheral PP (figure 4)[1] different methods (1 invasive, 1 used the generalized transfer functions, 3 calibrated the carotid waveform from mean and diastolic peripheral BP) have been applied for the assessment of PP amplification. Only one study [5] provided negative results regarding the ability of central PP to predict the clinical outcome. This study [5] has been questioned in the past [6], by two of the co-authors of the present study [1], because in average negative PP amplification was reported i.e. a higher central than peripheral PP, most probably due to flaws in the calibration of the carotid waveform [6]. The authors [1] decided not to deal with potential methodological problems of the original studies, thus avoiding to introduce their personal expert's opinion [4, 6] in the metanalysis. They strictly followed the methodology of metanalysis and the non-consensus [4] on central PP assessment; they should be given recognition for that.

Our view is that on the basis of the above evidence [1][6] the exclusion of the aforementioned study [5] from the analysis (figure 4 [1]) might be a second reasonable approach and even provide more solid results. This is not necessary regarding AI since it is independent from BP calibration. Finally, the issue of heterogeneity commonly observed in metanalysis, suggests that the future clinical goal for central PP is the identification of those subgroups that will have a clear benefit regarding CV risk stratification and treatment. The final verdict is still to come, so far: "case not-closed".

Disclosures None

References

1. Vlachopoulos Ch, Aznaouridis K, O'Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J. 2010 Mar 2. [Epub ahead of print]

2. Avolio, A., L. Van Bortel, P. Boutouyrie, D.W. Cockcroft, C.M. McEniery, A.D. Protogerou, M.J. Roman, M.E. Safar, P. Segers, and H. Smulyan, The role of pulse pressure amplification in arterial hypertension: Experts' opinion and review of the Data. Hypertension 2009; 54:375-383.

3. Mahieu D, Rietzschel ER, De Buyzere ML, Verbeke F, Gillebert TC, De Backer G, Bacquer D, Verdonck P, Van Bortel LM, Segers P, on behalf of the Asklepios investigators. Noninvasive assessment of central and peripheral arterial pressure (waveforms): implications of calibration methods. J Hypertens. 2010; 28:300-5

4. Avolio AP, Van Bortel LM, Boutouyrie P, Cockcroft JR, McEniery CM, Protogerou AD, Roman MJ, Safar ME, Segers P, Smulyan H. Response to Central Pressure and Pulse Wave Amplification in the Upper Limb Hypertension; 2010: 55: e3.

5. Dart AM, Gatzka CD, Kingwell BA, Willson K, Cameron JD, Liang YL, Berry KL, Wing LMH, Reid CM, Ryan P, Beilin LJ, Jennings GLR, Johnston CI, McNeil JJ, MacDonald GJ, Morgan TO, West MJ. Brachial blood pressure but not carotid arterial waveforms predict cardiovascular events in elderly female hypertensives. Hypertension. 2006;47:785-790.

6. O'Rourke MF, Nichols WW, Safar ME. Effects of Angiotensin- Converting Enzyme Inhibitors on Central Blood Pressure. Hypertension. 2007 Sep;50(3):e63; author reply e64.

Conflict of Interest:

None declared