Response to Letters Regarding Article, “Differential Impact of Blood Pressure-Lowering Drugs on Central Aortic Pressure and Clinical Outcomes: Principal Results of the Conduit Artery Function Evaluation (CAFE) Study”
We respond to recent correspondence relating to the Conduit Artery Function Evaluation study (CAFE),1 published in Circulation earlier this year.
We thank Drs Nieminen, Kahonen, and Kobie for their remarks and suggestions. We agree that increased stroke volume at lower heart rates should be considered as a contributor to the elevated pulse pressure (PP) seen with atenolol-based treatment in the CAFE study. We did not assess stroke volume, and further studies are required to define the impact of blood pressure (BP)-lowering therapies on stroke volume and its contribution to central aortic pressures. Nevertheless, our data do suggest an important role for increased wave reflections in determining higher central aortic pressures with atenolol-based when compared with amlodipine-based treatment. Indeed, the higher central but not brachial PP with atenolol-based therapy in the CAFE study supports the hypothesis that the main driver of differential central aortic pressures was drug effects on pressure wave reflections rather than changes in stroke volume.
We agree with Drs Safar and Fournier that the findings of the CAFE study are consistent with their report of differential drug effects on central aortic pressures in the Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind Study (REASON).2 We concur with the view that vascular structural changes are likely to make an important contribution to the long-term hemodynamic effects of BP-lowering therapy, especially wave reflection, and we suggested in our article that different BP-lowering treatments may modify central aortic pressures and hemodynamics through differential effects on vascular structure.1 The fact that the most beneficial effects on central aortic pressure have been observed with vasodilator therapy, in contrast to β-blockade, supports the view that a reduction in vascular resistance, by vasodilation and subsequent vascular remodeling, is an important determinant of reduced wave reflection and central aortic pressure, thereby defining the characteristics of optimal BP-lowering therapy.
Cameron and colleagues are concerned that the data in their article3 may have been misinterpreted. We clarify that our reference to their work related to the accuracy and validation of the transfer function rather than the derivation of central aortic pressures, which are prone to and dependent on the same level of inaccuracy as the measurement of brachial BP by cuff sphygmomanometry.
We thank Dr Dart et al for their comments and interest in our study but would like to point out fundamental differences between the design and objectives of the CAFE study and The Australian National Blood Pressure Study 2 (ANBP2). substudy of central aortic pressures.4 The prespecified primary objective5 of the CAFE study was to examine the hypothesis that 2 different BP-lowering regimens would have different effects on derived central arterial pressures and hemodynamics despite similar effects on brachial pressures. This was convincingly demonstrated by the findings of the CAFE study. There is now understandably much interest in the relative importance of on-treatment central aortic BP and PP versus brachial BP and PP as determinants of clinical outcomes.
A secondary objective of the CAFE study was to explore the relation between central aortic pressures and clinical outcomes, and we showed a significant relation between central aortic PP and the composite clinical outcome using Cox proportional hazards modeling. We recognized the limited statistical power of this secondary analysis, and, mindful of the fact that the end point comprised only 305 events, we attached appropriate cautions to our interpretation of this result.
In contrast, the ANBP2 substudy4 examined the relation between baseline blood pressures and clinical outcomes in fewer than 500 people, all of whom were women, accumulating only 53 events. The ANBP2 substudy did not show a significant relation between baseline central aortic pressures and clinical outcomes. However, there are problems with the confidence of the authors in dismissing the importance of central aortic pressures: (1) The ANBP2 substudy was underpowered to test a clinical outcomes hypothesis and thus prone to a type 2 statistical error; and (2) baseline central aortic pressures are not the issue—importantly, the CAFE study showed that the kind of treatments used to lower BP can differentially influence central aortic pressures. This addressed the more important question regarding on treatment brachial versus central aortic pressures. This is the key question, and the ANBP2 substudy does not contribute to this debate.
Finally, we agree with the commentary of Oparil and Izzo6 that uncertainty remains regarding the utility of radial artery tonometry in routine clinical practice. We would go further and suggest that the findings of the CAFE study prompt the need for further studies to more effectively evaluate the effects of BP-lowering drugs and other agents with the potential to influence central aortic pressures and hemodynamics in clinical trials. In so doing, such suitably powered studies would define the relative importance of central aortic versus brachial pressures with regard to clinical outcomes.
Drs Williams, Cruickshank, Collier, Stanton, Thom, and Hughes have received research funding from Pfizer. Dr O’Rourke is the founder and medical director and a board member of Atcor Medical. Dr O’Rourke also holds shares in Atcor Medical. Drs Lacy and Thurston have no conflicts of interest to disclose.
Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, Hughes AD, Thurston H, O’Rourke M. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) Study. Circulation. 2006; 113: 1213–1225.
Asmar RG, London GM, O’Rourke ME, Safar ME, REASON Project Coordinators and Investigators. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension. 2001; 38: 922–926.
Hope SA, Meredith IT, Cameron JD. Effect of non-invasive calibration of radial waveforms on error in transfer-function-derived central aortic waveform characteristics. Clin Sci. 2004; 107: 205–211.
Dart AM, Gatzka CD, Kingwell BA, Willson K, Cameron JD, Liang YL, Berry KL, Wing LM, Reid CM, Ryan P, Beilin LJ, Jennings GL, 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.
Oparil S, Izzo JL Jr. Pulsology rediscovered: commentary on the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006; 113: 1162–1163.