Lots of stuff packed into that name: industry sponsorship (Merck, the makers of Losartan), the hypothesis (ATII blockade would reduce endpoints) and the nephrologic bent of the study (two of the primary composite end point components were renal outcomes, doubling of serum Cr and reaching ESRD).
The trial was international with multiple participating centers. 1513 patients were randomized.
To be included you needed to be between 31 and 70 years old and have DMII with diabetic nephropathy defined as macroalbuminuria (spot urine albumin/Cr of >300 in mg/g) and a Cr between 1.3-3.0 mg/dl (higher Cr's were required for men of at least 60 kg's).
Exclusion criteria were DMI, non-diabetic kidney disease, an MI or CABG one month prior to enrollment, CVA or PTCA with 6 months, TIA within one year or any history of CHF.
Mean followup time was meant to be 4.5 years after the final enrolled patient but the study ended early (mean followup 3.4 years) after data emerged that RAAS blockade with ACE inhibitors provided cardiovascular protection to patients with CKD including those with DMII.
Baseline characteristics were similar between groups. A couple things did stand out to me on this reading that I hadn't appreciated before...
1) Patients were quite proteinuric. This was by no means a trial of DMII patients with microalbuminuria.
2) Most patients were CKD III. If you take the mean serum Cr's of 1.9 mg/dl in the two groups and plug them into the MDRD most participants (non-African American) using the mean age of 60 had mean eGFRs of around 39 ml/min/1.73m2.
Interestingly two standard deviations below yields a serum Cr of 0.9 mg/dl which would seem to fall outside the inclusion criteria. I suppose older women with values around this could fall into CKD III by MDRD and perhaps this is what drove it. I'll have to look back at the study description paper to sort this out.
Patients received antihypertensive regimens that included either Losartan started at 50mg and increased to 100mg qday or placebo. The breakdown by classes of medications used in each group is shown below...
You can see that slightly more of all the classes other than ARBs (and ACEs which were excluded) were used in the placebo group. Makes sense as at the end of the study there was no significant difference between the two groups in terms of BP (though there was a small trough time averaged difference in BP between the ARB and placebo group which did not significantly alter outcomes).
The primary outcome was the composite of doubling of serum Cr, ESRD (defined as need for prolonged dialysis or transplant) or death (defined as failure to call back Barry Brenner).
The secondary outcomes included a cardiovascular composite (MI, stroke, first hospitalization for angina or CHF, coronary or peripheral revascularization or death from any of the above), progression of renal disease and change in proteinuria.
Discontinuation of ARB and placebo due rise in serum Cr occurred in 1.5% and 1.2% of patients respectively. Similarly discontinuation due to hyperkalemia occurred in 1.1% and 0.5% of patients respectively. (Amazing how low these are in studies.)
Overall though, 53.5% and 46.5% of patients in the placebo and ARB groups stopped their study drug. Given this it's amazing how large effects remained in the intention to treat analysis.
The primary outcome occurred in 47.1% of the placebo group and 43.5% in the ARB group for an ARR of 3.6% and a RRR 16%. This was driven by the two renal endpoints as mortality was equal between the two group with 1 in 5 patients (!) in both groups passing on. The effect was larger when looking at those who actually stayed on rx with the RRR growing to 22%.
There was no difference in the cardiovascular composite with roughly 1/3rd of both groups experiencing one of these outcomes though there were significantly less 1st hospitalizations for heart failure in the ARB group.
The authors speculate that this may have been due to the relatively low cardiovascular risk produced by exclusion criteria which is a little tough to see when 1/3rd of patients are having an event in just 3.4 years of followup.
There was a significant reduction in the rate of GFR decline in the ARB when compared with placebo with the groups losing 4.4 ml/min/1.73m2 and 5.2 ml/min/1.73m2 per year respectively.
According to the discussion the above translates to roughly a 2 year delay to the time to need for dialysis or transplantation.
Proteinuria was also reduced by 35% in the ARB group.
So nutshell...
Big international muticenter ARB vs placebo trial with intention to treat analysis of diabetic nephropathy with macroalbuminuria showing reduction in a combined endpoint of mortality, ESRD or doubling of serum Cr driven by the two renal outcomes.
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