ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs)



















CHARM-ALT trial - Candesartan vs Placebo in Heart Failure with Reduced EF, Lancet (2003) [PubMed abstract]
  • The CHARM-ALT trial enrolled 2028 patients with heart failure who were not taking an ACE inhibitor
Main inclusion criteria
  • NYHA II - IV heart failure
  • EF ≤ 40%
  • Intolerant to ACE inhibitors
Baseline characteristics
  • Average age 66 years
  • Average EF - 30%
  • Average BP - 130/77 mmHg
  • NYHA class: II - 48% | III - 49% | IV - 3.6%
  • Heart failure type: Ischemic - 68% | Idiopathic - 19% | Hypertensive - 6%
  • Baseline meds: Diuretic - 85% | Beta blocker - 55% | Spironolactone - 24%
  • Reason for ACE intolerance: Cough - 72% | Hypotension - 13% | Renal dysfunction - 11% | Other - 10%
Randomized treatment groups
  • Group 1 (1013 patients) - Candesartan with a target dose of 32 mg once daily (average dose at 6 months was 23 mg)
  • Group 2 (1015 patients) - Placebo once daily
  • Candesartan was started at a dose of 4 - 8 mg once daily and doubled at a minimum of every 2 weeks to a target of 32 mg
Primary outcome: Cardiovascular death or unplanned admission to hospital for the management of worsening heart failure
Results

Duration: Median of 33.7 months
Outcome Candesartan Placebo Comparisons
Primary outcome 33% 40% HR 0.77, 95%CI [0.67 - 0.89], p=0.0004
Overall mortality 26.2% 29.2% HR 0.87, 95%CI [0.74 - 1.03], p=0.11
Hospitalization for heart failure 20.9% 28.7% p=0.0001
Drug discontinuation 24% 22% p=0.49
Hypotension causing drug discontinuation 3.7% 0.9% p<0.0001
Increase in creatinine causing drug discontinuation 6.1% 2.7% p<0.0001
Hyperkalemia causing drug discontinuation 1.9% 0.3% p=0.0005
  • At 6 months, blood pressure had decreased by 4.4/3.9 mmHg more in the candesartan group than in the placebo group

Findings: Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors
VALIANT Trial - Valsartan vs Captopril vs Both in Heart Failure with Reduced EF, NEJM (2003) [PubMed abstract]
  • The VALIANT trial enrolled 14,703 patients with acute myocardial infarction that was complicated by heart failure or left ventricular dysfunction
Main inclusion criteria
  • Myocardial infarction within past 0.5 - 10 days
  • Clinical or radiologic signs of heart failure or EF < 35% on ECHO or < 40% on radionuclide ventriculography
Main exclusion criteria
  • SBP < 100
  • Serum creatinine ≥ 2.5 mg/dl
  • Previous intolerance to ACE or ARB
  • Significant heart valve disease
Baseline characteristics
  • Average age 65 years
  • Average BP - 122/72
  • Average EF - 35%
  • History of prior heart failure - 15%
  • Received PCI - 35%
  • Baseline meds: ACE/ARB - 41% | Beta blocker - 70% | Diuretics - 60%
Randomized treatment groups
  • Group 1 (4909 patients) - Valsartan with a target dose of 160 mg twice a day (mean dose achieved 247 mg/day)
  • Group 2 (4885 patients) - Valsartan with a target dose 80 mg twice daily + Captopril with a target dose 50 mg three times a day (mean dose achieved 116 mg/day and 105 mg/day, respectively)
  • Group 3 (4909 patients) - Captopril with a target dose of 50 mg three times a day (mean dose achieved 117 mg/day)
  • Initial valsartan dose was 20 mg and initial captopril dose was 6.25 mg. Study drugs were titrated to target over a 3-month period if possible.
Primary outcome: All-cause mortality
Results

Duration: Median of 24.7 months
Outcome Valsartan Val + Cap Captopril Comparisons
Primary outcome 19.9% 19.3% 19.5% 1 or 2 vs 3 p>0.50
Hospitalization for myocardial infarction or heart failure 18.7% 17.1% 19.3% 1 vs 3 p=0.50 | 2 vs 3 p=0.005
Hypotension causing drug discontinuation 1.4% 1.9% 0.8% 1 or 2 vs 3 p<0.05
Renal dysfunction causing drug discontinuation 1.1% 1.3% 0.8% 1 vs 3 p>0.05 | 2 vs 3 p<0.05
Hyperkalemia causing drug discontinuation 0.1% 0.2% 0.1% 1 or 2 vs 3 p>0.05
Cough causing drug discontinuation 0.6% 2.1% 2.5% 1 vs 3 p<0.05 | 2 vs 3 p>0.05
Drug discontinuation due to any adverse event 5.8% 9% 7.7% 1 or 2 vs 3 p<0.05
Average blood pressure at 1 year 127/75 125/75 127/76 N/A

Findings: Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival.





CSG Trial - Irbesartan vs Amlodipine vs Placebo in Diabetic Kidney Disease, NEJM (2001) [PubMed abstract]
  • The CSG trial enrolled 1715 diabetics with hypertension and proteinuria
Main inclusion criteria
  • Age 30 - 70 years
  • Type 2 diabetes
  • Treated hypertension or untreated BP > 135/85
  • Proteinuria ≥ 900 mg/day
  • Serum creatinine 1 - 3 mg/dl in women or 1.2 - 3 mg/dl in men
Baseline characteristics
  • Average age 59 years
  • Average BP - 159/87
  • Average serum creatinine - 1.67 mg/dl
  • Median 24-hour protein - 2.9 grams
  • Average A1C - 8.2%
Randomized treatment groups
  • Group 1 (579 patients) - Irbesartan 75 - 300 mg once daily
  • Group 2 (567 patients) - Amlodipine 2.5 - 10 mg once daily
  • Group 3 (569 patients) - Placebo
  • Patients were treated to a target BP of < 135/85. Non-study ACE inhibitors, ARBs, and calcium channel blockers were not allowed.
Primary outcome: Composite of doubling of the baseline serum creatinine concentration, the development of end-stage renal disease, or death from any cause
Results

Duration: Average of 2.6 years
Outcome Irbesartan Amlodipine Placebo Comparisons
Primary outcome 32.6% 41.1% 39% 1 vs 2 p=0.005 | 1 vs 3 p=0.03
End-stage renal disease 14.2% 18.3% 17.8% 1 vs 2 p=0.06 | 1 vs 3 p=0.19
Doubling of serum creatinine 16.9% 25.4% 23.7% 1 vs 2 p<0.001 | 1 vs 3 p=0.009
Overall mortality 15% 14.6% 16.3% 1 vs 2 p=0.75 | 1 vs 3 p=0.69
Hyperkalemia leading to drug discontinuation 1.9% 0.5% 0.4% 1 vs 2 p=0.01 | 1 vs 3 p=0.01
Average blood pressure during trial 140/77 141/77 144/80 N/A
  • Amlodipine was not significantly better than placebo for any measured outcome

Findings: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.
ROADMAP Trial - Olmesartan vs Placebo for the Prevention of Diabetic Kidney Disease, NEJM (2011) [PubMed abstract]
  • The ROADMAP trial enrolled 4447 diabetics without proteinuria
Main inclusion criteria
  • Type 2 diabetes
  • Normoalbuminuria (UACR [mg/g]: ≤ 35 for females, ≤ 25 for males)
  • At least one of the following - dyslipidemia, hypertension, obesity, smoker, or high waist circumference
Main exclusion criteria
  • CrCl < 30 ml/min
  • SBP > 200, DBP > 110
  • Treatment with ARB or ACE inhibitor within last 6 months
  • Cardiovascular event within 6 months
  • Renal-vascular disease
Baseline characteristics
  • Average age 58 years
  • Average A1C - 7.7%
  • Average BP 136/81
  • Average GFR 85 ml/min
  • Average duration of diabetes - 6.1 years
Randomized treatment groups
  • Group 1 (2232 patients) - Olmesartan 40 mg once daily
  • Group 2 (2215 patients) - Placebo
  • ACE inhibitors and non-study ARBs were not allowed in either group. Other classes of BP meds were allowed.
  • Patients were treated to a target BP of 130/80
Primary outcome: Development of microalbuminuria
Results

Duration: Median of 3.2 years
Outcome Olmesartan Placebo Comparisons
Primary outcome 8.2% 9.8% HR 0.77, 95%CI [0.63 - 0.94], p=0.01
Doubling of serum creatinine 1% 1% p>0.05
Overall mortality 1.2% 0.7% HR 1.70, 95%CI [0.90 - 3.22], p=0.10
Hypotension 2.6% 0.3% p<0.001
Hyperkalemia 0.5% 0.4% p=0.50
  • The olmesartan group had a lower average blood pressure during the study - SBP lower by 3.3 mmHg and DBP lower by 1.3 mmHg
  • When the results were adjusted for the lower blood pressure achieved in the olmesartan group, the statistical significance became borderline nonsignificant (p=.08 for SBP, p=0.06 for DBP)

Findings: Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern.










CHARM-ADDED Trial - Candesartan + ACE Inhibitor vs ACE Inhibitor in Heart Failure, Lancet (2003) [PubMed abstract]
  • The CHARM-Added trial enrolled 2548 patients with NYHA class II-IV heart failure who were being treated with an ACE inhibitor
Main inclusion criteria
  • EF ≤ 40%
  • NYHA class II - IV heart failure (if NYHA class II had to have had hospitalization for cardiac reasons within 6 months)
  • Treatment with ACE inhibitor
Baseline characteristics
  • Average age 64 years
  • Average EF - 28%
  • NYHA class: II - 24% | III - 73% | IV - 3%
  • Heart failure type: Ischemic - 63% | Idiopathic - 27% | Hypertensive - 6.5%
  • Baseline meds: ACE inhibitor - 100% | Diuretic - 90% | Beta blocker - 56% | Spironolactone - 17%
Randomized treatment groups
  • Group 1 (1276 patients) - Candesartan target dose of 32 mg once daily (mean dose at 6 months was 24 mg)
  • Group 2 (1272 patients) - Placebo once daily
  • Candesartan was started at 4 - 8 mg once daily and doubled every 2 weeks to a target of 32 mg if tolerated
Primary outcome: Composite of cardiovascular death or hospitalization for heart failure
Results

Duration: Median of 41 months
Outcome Candesartan Placebo Comparisons
Primary outcome 37.9% 42.3% HR 0.85, 95%CI [0.75 - 0.96], p=0.011
Hospitalization for heart failure 25.3% 30% p=0.002
Overall mortality 30% 32% HR 0.89, 95%CI [0.77 - 1.02], p=0.086
Drug discontinuation for adverse event 24% 18% p=0.0003
Hypotension leading to drug discontinuation 4.5% 3.1% p=0.079
Increase in creatinine leading to drug discontinuation 7.8% 4.1% p=0.0001
Hyperkalemia leading to drug discontinuation 3.4% 0.7% p<0.0001
  • At 6 months, SBP and DBP were reduced more from baseline in the candesartan group than in the placebo group (difference in reduction 4.6/3 mmHg)

Findings: The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction