1. Title:
Renal Sub-study of INVEST (INternational VErapamil SR/Trandolarpil STudy)

2. Investigators:
Principal Investigators:
Carl J. Pepine, M.D., Professor and Chief, Division of Cardiovascular Medicine
George Bakris, M.D., Professor and Section Director, Department of Preventive
Medicine, Rush-Presbyterian-St Lukes Medical Center
Co-Investigators:
JogiRaju Tantravahi, M.D., Division of Renal Medicine
Rhonda Cooper-DeHoff, Pharm D, Division of Cardiovascular Medicine
Eileen Handberg, Ph D, ARNP, Division of Cardiovascular Medicine
Chris Arant, M.D. Division of Cardiovascular Medicine
Jose Cangiano, M.D.

3. Abstract:
In the United States, approximately 424,000 people have end stage renal failure (ESRD), which accounts for 67,000 deaths each year, the majority of which are due to atherosclerosis. The incidence of ESRD has continued to grow over the past two decades. The major etiologies of ESRD are diabetes, hypertension and atherosclerosis. Coronary artery disease (CAD) and cerebrovascuclar disease are enormous public health concerns, accounting for most of the death and disability in the US and other developed countries. Small studies with follow-up of more than three years have suggested that verapamil SR, a member of the non-dihydropyridine calcium antagonist class of antihypertensive medications, slows progression of pre-existing renal dysfunction. This sub-study of INVEST will test whether an antihypertensive treatment strategy initiated with verapamil SR in a large population of patients CAD, slows progression/or development of renal dysfunction compared with an antihypertensive treatment strategy initiated with the beta adrenergic blocker atenolol. Laboratory data obtained at or about the time of enrollment in the INVEST will be retrieved from the records of enrolled patients. These laboratory data will be repeated at study exit. The data will include serum creatinine, BUN, albumin, and urine protein. The primary outcome variable will be glomerular filtration rate (GFR) at study exit, estimated from these data and the patient’s age, ethnicity and body weight.

4. Specific Aims:
The hypothesis is that initial treatment with a verapamil-based antihypertensive regimen will prevent significant decline in GFR as compared to an initial antihypertensive treatment with atenolol and/or hydrochlorothiazide.

The primary outcome variable is the difference in GFR at study exit. GRF will be calculated by using the Levey modification of the Cockroft and Gault formula (4). To ensure the comparability of the two groups, GFR will also be calculated from baseline values and tested for equality.

The secondary outcome will include the proportion of patients who have a doubling of their serum creatinine or reduction in glomerular filtration rate by 50%, when compared to values obtained at baseline.

Other outcomes will include:

• The proportion of patients who die or have a ? 25% increase in their serum creatinine or a ? 12.5% decrease in their GFR

• The proportion of patients who die or have a ? 50% increase in their serum creatinine or a ? 25% decrease in their GFR

• The proportion of patients who die or have a ? 100% increase in their serum creatinine or a ? 50% decrease in their GFR

• The mean serum creatinine value at baseline compared to end of study

• The mean GFR at baseline compared to end of study

• The total number of patients with an increase in serum creatinine

• The total number of patients with a reduction in GRF

5. Background and Significance:
Cardiovascular disease is the number one cause of death in the USA and other developed countries. Patients with ESRD and cardiovascular disease, particularly those with diabetes, have a higher mortality rate than those without ESRD. Reports have evaluated the use of the nondihydropyridine ^(1,2) and dihydropyridine ⁽³⁾ calcium antagonist classes of antihypertensive agents for the ability to prevent the progression of renal dysfunction. In non-insulin dependent hypertensive diabetics randomized to receive either an ACE inhibitor (AI), a nondihydropyridine calcium antagonist (NDCA) or a beta blocker (BB), there was similar blood pressure lowering and slowing of progression of renal disease between the NDCA and AI groups, while the BB group did not have slowing of renal disease progression despite adequate blood pressure control. ⁽¹⁾ However, in a study comparing two different dihydropyridine calcium antagonist (DCA) in hypertensive diabetics with renal disease followed over one year, neither DCA slowed the progression of renal disease either by reducing albuminuria or proteinuria, despite adequate blood pressure control. ⁽³⁾

The renal sub-study of INVEST will further evaluate the use of a NDCA in patients with CAD and hypertension with regard to the diminished progression of renal disease, and will further substantiate the data already available in diabetics. Twenty eight percent of the patients enrolled in the INVEST were diabetic at baseline, and many more have been diagnosed with diabetes since enrollment. If this sub-study shows that patients with CAD and hypertension who have been treated with a NDCA have a delay in development or progression of, renal dysfunction, especially in the diabetics, this would serve as important new information in these very high risk patients with increased morbidity and mortality.

The INVEST collected data on each patient when they were enrolled regarding whether they had renal insufficiency at the time of enrollment and whether or not they had severe renal disease (SCr ? 4mg/dl) which was an exclusion. This sub-study will record the laboratory data from the medical record that allowed the site investigator to answer these questions. In addition, blood and urine samples will be collected from patients upon closeout from the INVEST, to provide current SCr, BUN, albumin and protein values. From these retrospective and prospective data, glomerular filtration rate will be calculated using the Cockroft and Gault equation with Levey modification. ⁽⁴⁾

References:

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

2. Bakris GL, Mangrum A, Copley JB, Vicknair N, Sadler R. Effect of calcium channel or beta-blockade on the progression of diabetic nephropathy in African Americans. Hypertension 1997; 29(3):744-750.

3. 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.

4. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130(6):461-470.

6. Research Plan:
Patient Eligibility

A. Inclusion Criteria
1. Age ? 50 years, currently enrolled in the INVEST
2. History of coronary artery disease as defined in the INVEST inclusion criteria
3. Written informed consent for renal sub-study data

B. Exclusion Criteria
1. Not participating in the INVEST (dead or withdrew)
2. No informed consent

Study Design (See flow chart for study design overview)

The study will be conducted in 2 periods:

Period 1: Informed consent to participate will be offered to all patients who meet inclusion and exclusion criteria. If the patient agrees to participate and provides written informed consent, then a retrospective chart review to determine the patient’s serum creatinine, BUN, and/or albumin around the time of enrollment in the INVEST will be conducted. If these values are available in the patient’s medical chart they will be collected and reported. These retrospective laboratory values (if available), and the date they were obtained from the patient will be submitted by the site investigator to the INVEST database at the University of Florida through secure internet Web pages similar in design and function as those used currently for INVEST.

Period 2: At the time the patient is closed out from the INVEST, (beginning in November 2002), patients who have agreed to participate will have a single venous blood draw and provide a urine sample.

The blood will be analyzed for SCr, BUN and albumin and the urine will be analyzed for protein content. Those patients who have a rise in their SCr of 0.5mg/dl or more from their baseline value, will be asked to have a repeat blood draw to confirm the results. Additionally, a randomly selected subset of patients who do not have any changes in their values will be asked to return to have a repeat blood draw to confirm the results. Laboratory results will be transferred directly to the University of Florida INVEST database in a secure fashion using the same technology employed by the INVEST study. This data will be shared with the site investigators so they can add the information to their patient’s medical record.

Statistical Considerations
Listed in the table are the odds ratios that can be detected for specified sample size based on a two-sided test, with level of significance 0.05 and power of 0.80.

7. Discomforts and Risks:
The risks and discomforts associated with this study are those that result from the blood draw. Those risks include discomfort at the site of puncture; possible bruising and swelling around the puncture site; rarely an infection; and, uncommonly, faintness from the procedure. A total of 10 ml of blood will be drawn once or twice, depending on the patient circumstance, as described above.

8. Benefits:
The patient will benefit from having a current laboratory evaluation of their renal function. Patients with heart disease will benefit in the future from the information learned relating to the use of verapamil SR and the onset or progression of renal dysfuntion.

9. Financial Risks:
There are no financial risks associated with this study. The patients will not be charged for the laboratory tests.

10. Financial Benefits:
Patients will receive compensation of their time and effort in providing the the blood and urine sample. If the patient is required to provide a second sample (as outlined in the protocol above) the patient will receive an additional compensation

11. Conflict of Interest:
There is no conflict of interest involved with this study beyond the professional benefit from academic publication or presentation of the results.