Critically Appraised Topic

Anthea Wang, 9/27/01

Brenner BM et al. Effects of Losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. NEJM 2001; 345(12): 861-869.

Clinical Question: A patient with DM and HTN who develops angioedema while taking ACE-I. Are ARBs as effective in preventing renal and cardiovascular outcomes? (Could it also cause angioedema?)

Background: Diabetic nephropathy leading to ESRD and cardiovascular disease are common complications of diabetes. There has been data showing that the interruption of the rennin-angiotensin system with ACE-I slows the progression of renal disease in patients with Type 1 diabetes, but similar data is not available with Type 2 diabetes.

A few studies have compared Captopril and Losartan in elderly patients looking at cardiovascular mortality and renal outcomes- ELITE and ELITEII. The RESOLVD Pilot Study compares Enalapril vs Cadesartan vs both.

Study Design: randomized, double-blinded trial comparing Losartan 50-100 mg/day to placebo, both in addition to conventional anti-hypertensives (calcium channel blockers, diuretics, alpha blockers, beta blockers, and centrally acting agents).

Patients

Inclusion criteria:

• 1513 patients were enrolled from 250 centers from 28 participating countries
• Age 31-70 years
• Type 2 diabetes
• Nephropathy (urine albumin to urine creatinine ratio > 300 or rate of urine protein excretion of 0.5 g/day and serum creatinine between 1.3-3.0)

Exclusion criteria:

• MI or CABG within the previous month or PTCA within the previous 6 months
• CVA within the previous 6 months or TIA within the previous year
• H/o heart failure before enrollment

No significant differences between placebo and intervention group (table 1). Good mix of races, although Caucasians still predominate (~50%)

Intervention

Losartan vs placebo in addition to other antihypertensives except ACE-I. ACE-Is or ARBs were discontinued and replaced by alternative open-label antihypertensive medications. Target blood pressure was 140/90. After the first four weeks, the dosage of Losartan or placebo was doubled. After eight weeks, other antihypertensives were added or their doses adjusted.

Patients received standard of care for diabetes including lab tests for HGBA1C and regular Q3 month visits.

Outcomes

Primary: Time to first event of composite endpoint

• Serum creatinine doubling

• ESRD
• Death

Secondary: Morbidity and mortality from cardiovascular causes

• MI
• Stroke
• First hospitalization for heart failure or unstable angina
• Coronary or peripheral revascularization
• Death from cardiovascular causes

Follow-up and analysis

• Follow-up was 3.4 years with study discontinued in February 2001 with the results of the HOPE trial that showed that Ramipril was effective in reducing the incidence of cardiovascular events in patients with renal impairment.
• Significant numbers of patients discontinued the study in the Losartan group and in the placebo group although more in the placebo group (46.5% and 53.5%), secondary to adverse events (17.2% and 21.7%), increase in creatinine (1.5% and 1.2%), increase in potassium (1.1% and 0.5%), withdrew consent (7.5% and 7.8). Not sure why the rest of the ~20% or so who discontinued the treatment.
• Only 3 patients were lost to follow-up.
• Intention to treat analysis

Results

Blood Pressure- trough blood pressure

	Baseline	First Year	Second Year	End of Study
Losartan	152/82 (105.5)	146/78 (100.9)	143/77 (99.1)	140/74 (95.9)
Placebo	153/82 (106.0)	150/80 (103.1)	143/77 (99.7)	142/74 (96.8)
	P=0.38	P<0.001	P=0.38	P=0.77

Regression analysis shows that even after correcting for BP, there were still significant differences in the Losartan group as compared to placebo when looking at the primary outcomes.

Primary Outcomes (Table 3)

For Primary Composite Endpoint:

	Composite reached	Composite not reached	Totals
Losartan	327	425	752	Y=327/752=0.435
Placebo	359	403	762	X+359/403=0.471
Totals	686	897	1514

RR=.435/.471=0.92 RRR=1-0.92=0.08=8%

ARR=0.471-0.435=0.036 NNT=1/0.036=28

Secondary Outcomes: The only significant result was the rate of first hospitalization for heart failure, which was 32% lower in the Losartan group.

Are the Results Valid?

• The assignment of patients to treatment was randomized.
• All the patients who entered the trial were accounted for at its conclusion, although it’s still disconcerting the number of patients who discontinued the study treatment both in the Losartan and placebo groups.
• Patients, clinicians, and study personnel were kept blinded to the intervention.
• The groups were similar at the start of the trial?
• The groups were treated equally aside from the intervention.

What are the Results?

• The primary outcome effects were significant as evidenced by the risk reductions given in Table 3. For cardiovascular morbidity and mortality, however,
• The treatment effect was also precise as evidenced by the confidence intervals given in Table 3.

Will the Results Help Me in My Patient Care?

• Some attributes of these patients are similar to mine: these were patients with higher-grade proteinuria and established renal insufficiency, they have baseline hypertension, and most of them were receiving antihypertensive medications. However, the study excluded patients with heart failure and patients at high risk for cardiovascular events. Also, a majority of the patients were Caucasians.
• The primary outcome of a composite of serum creatinine doubling, ESRD, and death was relevant. The secondary endpoints were just as relevant, but the study was not well designed to address the secondary endpoints. It had excluded patients with heart failure and those at high risk for cardiovascular events. The study could have better documented adverse events. Indirectly, it addressed the issue of adverse events by saying that the addition of Losartan did not increase the incidence of adverse events over placebo.
• When the patent on ACE-I runs out, it will become much cheaper than an ARB. However, if one can’t take ACE-I because of cough or angioedema, ARB would be the only choice to interrupt the rennin-angiotensin system. This study shows convincingly (beyond blood pressure reduction) that it is effective in improving renal outcomes in Type 2 diabetics, but not convincing in showing that it is effective in reducing cardiovascular outcomes. Also, what about the few reports of angioedema attributed to ARBs?