Beneficial effects on arterial stiffness and pulse-wave reflection of combined enalapril and candesartan in chronic kidney disease--a randomized trial

Marie Frimodt-Møller, Anne-Lise Kamper, Svend Strandgaard, Svend Kreiner, Arne Høj Nielsen, Marie Frimodt-Møller, Anne-Lise Kamper, Svend Strandgaard, Svend Kreiner, Arne Høj Nielsen

Abstract

Background: Cardiovascular disease (CVD) is highly prevalent in patients with chronic kidney disease (CKD). Inhibition of the renin-angiotensinsystem (RAS) in hypertension causes differential effects on central and brachial blood pressure (BP), which has been translated into improved outcome. The objective was to examine if a more complete inhibition of RAS by combining an angiotensin converting enzyme inhibitor (ACEI) and an angiotensin receptor antagonist (ARB) compared to monotherapy has an additive effect on central BP and pulse-wave velocity (PWV), which are known markers of CVD.

Methods: Sixty-seven CKD patients (mean GFR 30, range 13-59 ml/min/1.73 m(2)) participated in an open randomized study of 16 weeks of monotherapy with either enalapril or candesartan followed by 8 weeks of dual blockade aiming at a total dose of 16 mg candesartan and 20 mg enalapril o.d. Pulse-wave measurements were performed at week 0, 8, 16 and 24 by the SphygmoCor device.

Results: Significant additive BP independent reductions were found after dual blockade in aortic PWV (-0.3 m/s, P<0.05) and in augmentation index (-2%, P<0.01) compared to monotherapy. Furthermore pulse pressure amplification was improved (P<0.05) and central systolic BP reduced (-6 mmHg, P<0.01).

Conclusions: Dual blockade of the RAS resulted in an additive BP independent reduction in pulse-wave reflection and arterial stiffness compared to monotherapy in CKD patients.

Trial registration: Clinical trial.gov NCT00235287.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CONSORT Flowchart of the randomization…
Figure 1. CONSORT Flowchart of the randomization in the study.
Figure 2. The effect of dual blockade…
Figure 2. The effect of dual blockade compared to mono blockade on central systolic blood pressure with 95% confidence intervals as dotted lines.
The number of measurement indicates 1. for baseline (mix of patients with and without previous treatment with either ACEI/ARB), 2. after 8 weeks of mono blockade with either ACEI/ARB, 3. after further 8 weeks of mono blockade and 4. after 8 weeks of dual blockade. * P

Figure 3. The effect of dual blockade…

Figure 3. The effect of dual blockade compared with mono blockade on pulse-pressure-amplification with 95%…

Figure 3. The effect of dual blockade compared with mono blockade on pulse-pressure-amplification with 95% confidence intervals as dotted lines.
The number of measurement indicates 1. for baseline (mix of patients with and without previous treatment with either ACEI/ARB), 2. after 8 weeks of mono blockade with either ACEI/ARB, 3. after further 8 weeks of mono blockade and 4. after 8 weeks of dual blockade. * P

Figure 4. The effect of dual blockade…

Figure 4. The effect of dual blockade compared with mono blockade on heart rate adjusted…

Figure 4. The effect of dual blockade compared with mono blockade on heart rate adjusted Augmentation Index (AIxHR75) with 95% confidence intervals as dotted lines.
The number of measurement indicates 1. for baseline (mix of patients with and without previous treatment with either ACEI/ARB), 2. after 8 weeks of mono blockade with either ACEI/ARB, 3. after further 8 weeks of mono blockade and 4. after 8 weeks of dual blockade. * P
Similar articles
Cited by
References
    1. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, et al. (1999) Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99: 2434–2439. - PubMed
    1. London GM, Blacher J, Pannier B, Guerin AP, Marchais SJ, et al. (2001) Arterial wave reflections and survival in end-stage renal failure. Hypertension 38: 434–438. - PubMed
    1. Covic A, Haydar AA, Bhamra-Ariza P, Gusbeth-Tatomir P, Goldsmith DJ (2005) Aortic pulse wave velocity and arterial wave reflections predict the extent and severity of coronary artery disease in chronic kidney disease patients. J Nephrol 18: 388–396. - PubMed
    1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, et al. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342: 145–153. - PubMed
    1. Brenner BM, Cooper ME, de ZD, Keane WF, Mitch WE, et al. (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869. - PubMed
Show all 39 references
Publication types
MeSH terms
Associated data
Grant support
This work is funded by the Danish Kidney Association (Nyreforeningen), the Danish Society of Nephrology, The Danish Heart Association, the Research Council of Herlev Hospital, the Foundations of Augustinus, Hørslev, Aase and Ejnar Danielsen and Aase Bay, Denmark. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Follow NCBI
Figure 3. The effect of dual blockade…
Figure 3. The effect of dual blockade compared with mono blockade on pulse-pressure-amplification with 95% confidence intervals as dotted lines.
The number of measurement indicates 1. for baseline (mix of patients with and without previous treatment with either ACEI/ARB), 2. after 8 weeks of mono blockade with either ACEI/ARB, 3. after further 8 weeks of mono blockade and 4. after 8 weeks of dual blockade. * P

Figure 4. The effect of dual blockade…

Figure 4. The effect of dual blockade compared with mono blockade on heart rate adjusted…

Figure 4. The effect of dual blockade compared with mono blockade on heart rate adjusted Augmentation Index (AIxHR75) with 95% confidence intervals as dotted lines.
The number of measurement indicates 1. for baseline (mix of patients with and without previous treatment with either ACEI/ARB), 2. after 8 weeks of mono blockade with either ACEI/ARB, 3. after further 8 weeks of mono blockade and 4. after 8 weeks of dual blockade. * P
Similar articles
Cited by
References
    1. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, et al. (1999) Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99: 2434–2439. - PubMed
    1. London GM, Blacher J, Pannier B, Guerin AP, Marchais SJ, et al. (2001) Arterial wave reflections and survival in end-stage renal failure. Hypertension 38: 434–438. - PubMed
    1. Covic A, Haydar AA, Bhamra-Ariza P, Gusbeth-Tatomir P, Goldsmith DJ (2005) Aortic pulse wave velocity and arterial wave reflections predict the extent and severity of coronary artery disease in chronic kidney disease patients. J Nephrol 18: 388–396. - PubMed
    1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, et al. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342: 145–153. - PubMed
    1. Brenner BM, Cooper ME, de ZD, Keane WF, Mitch WE, et al. (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869. - PubMed
Show all 39 references
Publication types
MeSH terms
Associated data
Grant support
This work is funded by the Danish Kidney Association (Nyreforeningen), the Danish Society of Nephrology, The Danish Heart Association, the Research Council of Herlev Hospital, the Foundations of Augustinus, Hørslev, Aase and Ejnar Danielsen and Aase Bay, Denmark. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 4. The effect of dual blockade…
Figure 4. The effect of dual blockade compared with mono blockade on heart rate adjusted Augmentation Index (AIxHR75) with 95% confidence intervals as dotted lines.
The number of measurement indicates 1. for baseline (mix of patients with and without previous treatment with either ACEI/ARB), 2. after 8 weeks of mono blockade with either ACEI/ARB, 3. after further 8 weeks of mono blockade and 4. after 8 weeks of dual blockade. * P

References

    1. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, et al. (1999) Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99: 2434–2439.
    1. London GM, Blacher J, Pannier B, Guerin AP, Marchais SJ, et al. (2001) Arterial wave reflections and survival in end-stage renal failure. Hypertension 38: 434–438.
    1. Covic A, Haydar AA, Bhamra-Ariza P, Gusbeth-Tatomir P, Goldsmith DJ (2005) Aortic pulse wave velocity and arterial wave reflections predict the extent and severity of coronary artery disease in chronic kidney disease patients. J Nephrol 18: 388–396.
    1. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, et al. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342: 145–153.
    1. Brenner BM, Cooper ME, de ZD, Keane WF, Mitch WE, et al. (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869.
    1. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, et al. (2001) Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet 358: 2130–2131.
    1. Poulter NR, Wedel H, Dahlof B, Sever PS, Beevers DG, et al. (2005) Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet 366: 907–913.
    1. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, et al. (2002) Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359: 995–1003.
    1. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, et al. (2006) 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 113: 1213–1225.
    1. Hirata K, Vlachopoulos C, Adji A, O’Rourke MF (2005) Benefits from angiotensin-converting enzyme inhibitor ‘beyond blood pressure lowering’: beyond blood pressure or beyond the brachial artery? J Hypertens 23: 551–556.
    1. Wang KL, Cheng HM, Chuang SY, Spurgeon HA, Ting CT, et al. (2009) Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality? J Hypertens 27: 461–467.
    1. Roman MJ, Devereux RB, Kizer JR, Lee ET, Galloway JM, et al. (2007) Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the Strong Heart Study. Hypertension 50: 197–203.
    1. Pini R, Cavallini MC, Palmieri V, Marchionni N, Di BM, et al. (2008) Central but not brachial blood pressure predicts cardiovascular events in an unselected geriatric population: the ICARe Dicomano Study. J Am Coll Cardiol 51: 2432–2439.
    1. Mahmud A, Feely J (2000) Favourable effects on arterial wave reflection and pulse pressure amplification of adding angiotensin II receptor blockade in resistant hypertension. J Hum Hypertens 14: 541–546.
    1. Anan F, Takahashi N, Ooie T, Yufu K, Hara M, et al. (2005) Effects of valsartan and perindopril combination therapy on left ventricular hypertrophy and aortic arterial stiffness in patients with essential hypertension. Eur J Clin Pharmacol 61: 353–359.
    1. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, et al. (2008) Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 358: 1547–1559.
    1. Chan KE, Ikizler TA, Gamboa JL, Yu C, Hakim RM, et al. (2011) Combined angiotensin-converting enzyme inhibition and receptor blockade associate with increased risk of cardiovascular death in hemodialysis patients. Kidney Int 80: 978–985.
    1. Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, et al. (2001) The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 134: 663–694.
    1. National Kidney Foundation (2002) K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 39: S1–266.
    1. Pauca AL, O’Rourke MF, Kon ND (2001) Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension 38: 932–937.
    1. Laurent S, Cockcroft J, Van BL, Boutouyrie P, Giannattasio C, et al. (2006) Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 27: 2588–2605.
    1. Gallagher D, Adji A, O’Rourke MF (2004) Validation of the transfer function technique for generating central from peripheral upper limb pressure waveform. Am J Hypertens 17: 1059–1067.
    1. Weber T, Ammer M, Rammer M, Adji A, O’rourke MF, et al. (2009) Noninvasive determination of carotid-femoral pulse wave velocity depends critically on assessment of travel distance: a comparison with invasive measurement. J Hypertens 27: 1624–1630.
    1. Frimodt-Moller M, Nielsen AH, Strandgaard S, Kamper AL (2009) Feasibility of combined treatment with enalapril and candesartan in advanced chronic kidney disease. Nephrol Dial Transplant.
    1. Brochner-Mortensen J (1972) A simple method for the determination of glomerular filtration rate. Scand J Clin Lab Invest 30: 271–274.
    1. Brochner-Mortensen J, Freund LG (1981) Reliability of routine clearance methods for assessment of glomerular filtration rate in advanced renal insufficiency. Scand J Clin Lab Invest 41: 91–97.
    1. Avolio AP, Van Bortel LM, Boutouyrie P, Cockcroft JR, McEniery CM, et al. (2009) Role of pulse pressure amplification in arterial hypertension: experts’ opinion and review of the data. Hypertension 54: 375–383.
    1. Frimodt-Moller M, Nielsen AH, Kamper AL, Strandgaard S (2006) Pulse-wave morphology and pulse-wave velocity in healthy human volunteers: examination conditions. Scand J Clin Lab Invest 66: 385–394.
    1. Pannier B, Guerin AP, Marchais SJ, Safar ME, London GM (2005) Stiffness of capacitive and conduit arteries: prognostic significance for end-stage renal disease patients. Hypertension 45: 592–596.
    1. Safar ME, Blacher J, Pannier B, Guerin AP, Marchais SJ, et al. (2002) Central pulse pressure and mortality in end-stage renal disease. Hypertension 39: 735–738.
    1. Lemogoum D, Flores G, Van den Abeele W, Ciarka A, Leeman M, et al. (2004) Validity of pulse pressure and augmentation index as surrogate measures of arterial stiffness during beta-adrenergic stimulation. J Hypertens 22: 511–517.
    1. Nichols WW, Denardo SJ, Wilkinson IB, McEniery CM, Cockcroft J, et al. (2008) Effects of arterial stiffness, pulse wave velocity, and wave reflections on the central aortic pressure waveform. J Clin Hypertens (Greenwich) 10: 295–303.
    1. Protogerou AD, Papaioannou TG, Lekakis JP, Blacher J, Safar ME (2009) The effect of antihypertensive drugs on central blood pressure beyond peripheral blood pressure. Part I: (Patho)-physiology, rationale and perspective on pulse pressure amplification. Curr Pharm Des 15: 267–271.
    1. London GM, Pannier B, Guerin AP, Marchais SJ, Safar ME, et al. (1994) Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease: Comparative effects of ACE inhibition and calcium channel blockade. Circulation 90: 2786–2796.
    1. Dhakam Z, McEniery CM, Yasmin CockcroftJR, Brown MJ, et al. (2006) Atenolol and eprosartan: differential effects on central blood pressure and aortic pulse wave velocity. Am J Hypertens 19: 214–219.
    1. Mahmud A, Feely J (2002) Reduction in arterial stiffness with angiotensin II antagonist is comparable with and additive to ACE inhibition. Am J Hypertens 15: 321–325.
    1. Kamper AL, Thomsen HS, Nielsen SL, Strandgaard S (1990) Initial effect of enalapril on kidney function in patients with moderate to severe chronic nephropathy. Scand J Urol Nephrol 24: 69–73.
    1. Palmer BF (2004) Managing Hyperkalemia Caused by Inhibitors of the Renin-Angiotensin-Aldosterone System. N Engl J Med 351: 585–592.
    1. Bakris GL, Weir MR (2000) Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 160: 685–693.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner