Renal Sub study of INVEST

Investigating if treatment with Verapamil-based antihypertensive regimen will prevent significant decline in GFR compared to antihypertensive treatment with Atenolol and/or Hydrochlorothiazide.
Review the study protocol

INVEST provides a unique platform to extend investigation in many areas of Vascular Disease and Hypertension. We are currently in the process of developing other studies to this end with the most promising potential new study being a Renal Protection Trial.

BACKGROUND

The incidence of renal failure (ESRD) continues to grow over the past two decades¹. The major etiologies of ESRD are diabetes and hypertension¹. Coronary artery disease that results from diabetes and hypertension are enormous public health concerns, accounting for most of the death and disability in the US and many other countries. While long term studies have demonstrated a reduction in cardiovascular endpoints with the use of nondihydropyridine calcium antagonists such as verapamil in such populations, no such data exist for renal endpoints^2-5.

Small studies with long-term follow-up of more than three years have demonstrated verapamil SR, a non-dihydropyridine calcium antagonists slows progression of pre-existing renal dysfunction^6-10. Conversely, clinical trials with the dihydropyridine calcium antagonists, amlodipine, have failed to demonstrate a significant slowing of renal disease progression in those with renal insufficiency and proteinuria in both diabetic as well as non diabetic etiologies^11;12. Separate small studies have demonstrated that the combination of verapamil with an ACE inhibitor reduce proteinuria to a greater extent than an ACE inhibitor with dihydropyridine calcium antagonists at similar levels of blood pressure reduction^13;14. Moreover, an ongoing study will compare the effects of verapamil to amlodipine on proteinuria in nondiabetic renal disease in the presence of trandolapril¹⁵. Thus, no outcome trial on renal events has been performed to distinguish whether a combination that lowers proteinuria is better than a combination that doesn’t.

One proposed clinical trial would test whether a nondihydropyridine calcium antagonists, verapamil SR combined with the ACE inhibitor, trandolapril in a large population of participants with hypertension, coronary artery disease and renal insufficiency provides additional preservation of renal function over a dihydropyridine CA/ACE inhibitor combination.

Participants for the study will be selected at the termination of the INVEST trial, 2003 and will include INVEST participants, as well as new patients recruited for the trial. The protocol design is being developed and more details will be available shortly.

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Reference List

1. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000; 36(3):646-661.

2. Zanchetti A, Magnani B, Dal Palu C. Atherosclerosis and calcium antagonists: the VHAS. The Verapamil- Hypertension Atherosclerosis Study (VHAS) Investigators. J Hum Hypertens 1992; 6 Suppl 2:S45-S48.

3. Gheorghiade M, Goldstein S. Calcium-channel blockers in postmyocardial infarction patients with special notation to the Danish verapamil infarction trial II. Prog Cardiovasc Dis 1991; 34(1):37-43.

4. Gibson RS, Hansen JF, Messerli F, Schechtman KB, Boden WE. Long-term effects of diltiazem and verapamil on mortality and cardiac events in non-Q-wave acute myocardial infarction without pulmonary congestion: post hoc subset analysis of the multicenter diltiazem postinfarction trial and the second danish verapamil infarction trial studies. Am J Cardiol 2000; 86(3):275-279.

5. Hansen JF. [Verapamil therapy improves the prognosis after acute myocardial infarction. A review over the Danish studies of verapamil therapy during and after acute myocardial infarction]. Ugeskr Laeger 1992; 154(7):398-404.

6. Abbott K, Smith A, Bakris GL. Effects of dihydropyridine calcium antagonists on albuminuria in patients with diabetes. J Clin Pharmacol 1996; 36(3):274-279.

7. Mangrum A, Bakris GL. Predictors of renal and cardiovascular mortality in patients with non- insulin-dependent diabetes: a brief overview of microalbuminuria and insulin resistance. J Diabetes Complications 1997; 11(6):352-357.

8. Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996; 50(5):1641-1650.

9. Griffin KA, Picken MM, Bakris GL, Bidani AK. Class differences in the effects of calcium channel blockers in the rat remnant kidney model. Kidney Int 1999; 55(5):1849-1860.

10. Koshy S, Bakris GL. Therapeutic approaches to achieve desired blood pressure goals: focus on calcium channel blockers. Cardiovasc Drugs Ther 2000; 14(3):295-301.

11. Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285(21):2719-2728.

12. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345(12):851-860.

13. Bakris GL, Weir MR, DeQuattro V, McMahon FG. Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int 1998; 54(4):1283-1289.

14. Bakris GL, Griffin KA, Picken MM, Bidani AK. Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury. J Hypertens 1997; 15(10):1181-1185.

15. Boero R, Rollino C, Massara C, Vagelli G, Gonella M, Berto IM et al. Verapamil versus amlodipine in proteinuric non-diabetic nephropathies treated with trandolapril (VVANNTT study): design of a prospective randomized multicenter trial. J Nephrol 2001; 14(1):15-18.