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Michel Azizi and Joël Ménard CIRCULATIONAHA/2003/427070
Table I: Effects of dual blockade of the renin angiotensin system in randomized parallel group studies in patients with hypertension.
Author (year) / Patients / N /Drugs and doses
/ Treatment duration /Endpoints
(mg o.d.) / (months) / Change in BP / SafetyAzizi (2000) 1 / Essential hypertension
DBP: 95-115 mmHg / 177 / L 50
E10
L50+E10 / 1.5 / L50+E10 > L50 = E10 / L50+E10 was well tolerated with similar incidence of side effects between groups.
Mogensen (2000) 2 / Type 2 diabetes and hypertension
DBP: 90-110 mmHg Microalbuminuria. / 197 / C16
Lis 20
C16+Lis20 / 3 / C16+Lis20 > C16 = Lis20 / C16+Lis20 was well tolerated.
Cough incidence: <10%.
Ruilope (2000) 3 / Hypertensive or normotensive patients with progressive renal failure of various origin. / 109 / V160
V80+B5 or B10 *
V160+B5 or B10 * / 1.5 / V80+B5 or B10 > V160
V160+B5 or B10 > V160 / Dizziness in 5 cases during combined treatment.
Hyperkaliemia > 6 mmol/l: V160: n=1 vs combination: n=7.
Weir (2001) 4 / African-American hypertensive patients on high sodium diet.
DBP: 95-114 mmHg / 75 / V320
V160+HCTZ 12.5 V160+B20 / 1.5 / V160+HCTZ 12.5 >
V320 > V160+B20 / Not available.
Waeber (2002) 5 / Essential hypertension
non responsive to a 4 week-treatment with V80.
DBP: 95-114 mmHg / 148 / V80+B10 V80+HCTZ 12.5 / 1 / V80+B10 = V80+HCTZ / Cough incidence: V80+B10: 5% vs V80: 2%.
Sakata (2002) 6 / Essential hypertension
DBP: 90-105 mmHg
and /or SBP: 140-180 mmHg. / 65 / L50+Q10
Q10+Amlo 5 / 3 / L50+Q10 = Q10+Amlo 5 / Not available.
SBP/DBP: Systolic/diastolic blood pressure.
AT1 receptor antagonists: L: losartan, C: candesartan; V: valsartan.
ACE inhibitors: Lis: lisinopril; E: enalapril, B: benazepril; Q: quinapril. * the dose of benazepril was selected according to creatinine clearance.
HCTZ: hydrochlorothiazide; Amlo: amlodipine.
Table II: Effects of dual blockade of the renin angiotensin system in patients with incipient or overt diabetic nephropathy.
(year) / Patients / N /
Study
design
/ Drugsand doses / Treatment duration / Baseline / Endpoint
(mg o.d.) / (months) / BP / Ualb / GFR / BP / Ualb / GFR
(mmHg) / (g/24h) / (ml/min)
Mogensen
(2000) 2 / Type 2 diabetes, Hypertension,
Microalbuminuria. / 197 / Parallel
groups / C16
Lis20
Lis20+C16 / 3 / 163/96 / † / 86 / Lis20+C16 >
C16 = Lis 20 / Lis20+C16 = Lis20 > C16 / No change
Agarwal
(2001) 7 / Chronic nephropathy mainly of diabetes origin with persistent proteinuria despite Lis 40 for at least 3 months. / 16 / Crossover / L50
placebo / 1 / 156/88 / 3.6 / 69 / L50 = placebo / L50 = placebo / No change
Rossing
(2002) 8 / Type 2 diabetes,
Overt nephropathy,
Hypertension non responsive to a recommended dose of an ACE inhibitor. / 17 / Crossover / C8
placebo / 2 / 159/85 / 1.78 / 74 / C8 > placebo / C8 > placebo / Small decrease in GFR with C8. *
Jacobsen
(2002) 9 / Type 1 diabetes,
Overt nephropathy,
Hypertension non responsive to a recommended dose of an ACE inhibitor. / 21 / Crossover / I300
placebo / 2 / 156/87 / 1.87 / 52 / I300 > placebo / I300 > placebo / No change
Jacobsen
(2003) 10 / Type 1 diabetes,
Overt nephropathy non responsive to E40 for more than 3 months. / 24 / Crossover / I300
placebo / 2 / 131/74 / 0.52 / 65 / I300 > placebo / I300 > placebo / No change
Jacobsen
(2003) 11 / Type 1 diabetes,
Overt nephropathy. / 20 / Crossover / V80
B20
V80+B20 / 2 / 141/81 / 0.7 / 82 / V80+B20 >
V80 = B20 / V80+B20 > V80 = B20 / Small decrease in GFR with V80 + B20. *
BP: blood pressure; Ualb: urine albumin excretion; GFR: glomerular filtration rate.
AT1 receptor antagonists: C: candesartan; I: irbesartan; V: valsartan.
ACE inhibitors: B: benazepril; Lis: lisinopril; E: enalapril.
* Short-term decrease in GFR related to the larger decrease in SBP with the combination.
† Uabl/creatinine ratio: 6.2 mg/mmol
Table III: Effects of dual blockade of the renin angiotensin system in patients with non diabetic chronic nephropathy.
Study design
/ Drugsand doses / Treatment duration / Baseline / Endpoint
( mg o.d.) / (months) / BP / Proteinuria / GFR / BP / Proteinuria / GFR
(mmHg) / (g/24h) / (ml/min)
Russo
(2001) 12 / IgA nephropathy. / 10 / Crossover / E10, E20, L50, L100, L50+E10, L100+E20 / 1 / 127/73 / 1.5 / 110 / L100+E20 > L100 = L50 = E20 = E10 / L50+E10 > L100 = L50 = E20 = E10 / No change from baseline
Ferrari
(2002) 13 / Chronic GN. / 10 / Crossover / F20
I150
I150+F20 / 1.5 / 144/91 / 7.9 / 77 / I150+F20 > I150 = F20 / I150+F20 > I150 = F20 / No change from baseline
Berger
(2002) 14 / Chronic GN, Persistent proteinuria >1g/24h despite 3 months of standard doses of ACE inhibitor . / 12 / Crossover / C8
Placebo / 2 / 128/72 / 1.8 / 64 / C8 > placebo / C8 > placebo / No change from baseline
Campbell
(2003) 15 / Chronic nephropathy Hypertension,
Proteinuria > 1g/24h
GFR: 20-70 ml/min. / 23 / Crossover / V160
B20
V80 + B10 / 2 / 140/91 / 3.28 / 46 / V80+B10 = B20 = V160 / V80+B10 > B20 = V160 / No change from baseline
Nakao
(2003) 16 / Non diabetic chronic nephropathy. / 263 / Parallel
groups / T3
L100
L100+T3 / 48 / 130/76 / 2.5 / 37.5 / L100+T3 = T3 = L100 / L100+T3 >
T3 = L100 / L100+T3 reduced the incidence of time to doubling Screat. and ESRD more than L100 or T3.
GN: glomerulonephritis; BP: blood pressure; GFR: glomerular filtration rate; Screat: serum creatinine; ESRD: end stage renal disease
AT1 receptor antagonists: L: losartan; I: irbesartan; V: valsartan.
ACE inhibitors: E: enalapril; B: benazepril; F: fosinopril; T: trandolapril.
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Michel Azizi and Joël Ménard CIRCULATIONAHA/2003/427070
References for the tables
1. Azizi M, Linhart A, Alexander J, et al. Pilot study of combined blockade of the renin-angiotensin system in essential hypertensive patients. J Hypertens. 2000;18:1139-47.
2. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. Bmj. 2000;321:1440-4.
3. Ruilope LM, Aldigier JC, Ponticelli C, et al. Safety of the combination of valsartan and benazepril in patients with chronic renal disease. European Group for the Investigation of Valsartan in Chronic Renal Disease. J Hypertens. 2000;18:89-95.
4. Weir MR, Smith DH, Neutel JM, et al. Valsartan alone or with a diuretic or ACE inhibitor as treatment for African American hypertensives: relation to salt intake. Am J Hypertens. 2001;14:665-71.
5. Waeber B, Aschwanden R, Sadecky L, et al. Combination of hydrochlorothiazide or benazepril with valsartan in hypertensive patients unresponsive to valsartan alone. J Hypertens. 2001;19:2097-104.
6. Sakata K, Yoshida H, Obayashi K, et al. Effects of losartan and its combination with quinapril on the cardiac sympathetic nervous system and neurohormonal status in essential hypertension. J Hypertens. 2002;20:103-10.
7. Agarwal R. Add-on angiotensin receptor blockade with maximized ACE inhibition. Kidney Int. 2001;59:2282-9.
8. Rossing K, Christensen PK, Jensen BR, et al. Dual blockade of the renin-angiotensin system in diabetic nephropathy: a randomized double-blind crossover study. Diabetes Care. 2002;25:95-100.
9. Jacobsen P, Andersen S, Rossing K, et al. Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy. Nephrol Dial Transplant. 2002;17:1019-24.
10. Jacobsen P, Andersen S, Rossing K, et al. Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int. 2003;63:1874-80.
11. Jacobsen P, Andersen S, Jensen BR, et al. Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol. 2003;14:992-9.
12. Russo D, Minutolo R, Pisani A, et al. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am J Kidney Dis. 2001;38:18-25.
13. Ferrari P, Marti HP, Pfister M, et al. Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade. J Hypertens. 2002;20:125-30.
14. Berger ED, Bader BD, Ebert C, et al. Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition. J Hypertens. 2002;20:739-43.
15. Campbell R, Sangalli F, Perticucci E, et al. Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies. Kidney Int. 2003;63:1094-1103.
16. Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet. 2003;361:117-24.