ACE INHIBITORS














Captopril vs Others for Hypertension in Male Veterans, NEJM (1993) [PubMed abstract]
  • The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
  • Male veteran
  • DBP 95 - 109 mmHg off medications
Baseline characteristics
  • Average age 59 years
  • Average BP 152/99 mmHg
  • Black race - 48%
  • Current smoker - 32%
Randomized treatment groups
  • Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
  • Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
  • Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
  • Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
  • Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Placebo
  • There was a washout period of 4 - 8 weeks before randomization
  • Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results

Average BP reduction at the end of the titration phase (SBP/DBP mmHg)
HCTZ Atenolol Captopril Clonidine Diltiazem Prazosin Placebo
14 / 10 11 / 12 9 / 10 16 / 12 13 / 14 12 / 11 3 / 5
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • The incidence of side effects with captopril was similar to placebo

Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.





SOLVD Trial - Enalapril vs Placebo in Heart Failure with Reduced EF, NEJM (1991) [PubMed abstract]
  • The SOLVD trial enrolled 2569 patients with heart failure and an ejection fraction ≤ 35%
Main inclusion criteria
  • Congestive heart failure
  • EF ≤ 35%
  • Not taking an ACE inhibitor
Main exclusion criteria
  • Age > 80 years
  • Significant heart valve disease
  • Serum creatinine > 2 mg/dl
  • Myocardial infarction within a month
Baseline characteristics
  • Average age - 61 years
  • Average EF - 25%
  • Average BP - 125/77 mmHg
  • NYHA class: I - 11% | II - 57% | III - 30% | IV - 1.7%
  • Baseline meds: Diuretics - 85% | Digoxin - 67% | Beta blockers - 7.5% | Potassium-sparing diuretic - 9%
Randomized treatment groups
  • Group 1 (1284 patients) - Placebo twice a day
  • Group 2 (1285 patients) - Enalapril target dose of 10 mg twice a day (average dose 11.2 mg/day)
  • Eligible patients went through a run-in phase before randomization where they were given enalapril. Patients who could not tolerate enalapril were excluded.
  • Enalapril was started at 2.5 - 5 mg twice daily and titrated to 10 mg twice daily if tolerated
Primary outcome: All-cause mortality
Results

Duration: Average of 41.4 months
Outcome Placebo Enalapril Comparisons
Primary outcome 39.7% 35.2% RR 0.84, 95%CI [0.74 - 0.95], p=0.0072
Death or hospitalization for heart failure 57.3% 47.7% RR 0.74, 95%CI [0.66 - 0.82], p<0.0001
Hospitalization for cardiovascular reason 63% 57% p<0.001
Serum creatinine > 2 mg/dl 7.7% 10.7% p<0.01
Serum potassium > 5.5 mEq/L 2.5% 6.4% p<0.01
  • After 3 years, open-label ACE inhibitors were being used by 23% of patients in the placebo group
  • Blood pressure was significantly lower in the enalapril group by 4.7/4.0 mmHg over the course of the study

Findings: The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions.




PEACE Trial - Trandolapril vs Placebo in Patients with Stable CAD, NEJM (2004) [PubMed abstract]
  • The PEACE study enrolled 8290 patients with stable CAD and an EF > 40%
Main inclusion criteria
  • CAD documented by myocardial infarction, PCI, or CABG ≥ 3 months before enrollment, or ≥ 50% obstruction of coronary vessel on angiography
  • EF > 40%
  • Toleration of and compliance with trandolapril during run-in phase
Main exclusion criteria
  • Taking ACE/ARB
  • CABG or PCI within previous 3 months
  • Serum creatinine > 2 mg/dl
  • Potassium > 5.5 mEq/L
Baseline characteristics
  • Average age 64 years
  • History of PCI or CABG - 72%
  • Average BP - 134/78
  • Average EF - 58%
  • Baseline meds: Antiplatelet therapy - 90% | Lipid-lowering drug - 70% | Beta blocker - 60%
Randomized treatment groups
  • Group 1 (4158 patients) - Trandolapril target dose of 4 mg once daily
  • Group 2 (4132 patients) - Placebo once daily
  • Trandolapril was started at 2 mg once daily and increased to 4 mg after 6 months if tolerated
  • In the trandolapril group, 69% of patients achieved the 4 mg/day dose
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or coronary revascularization
Results

Duration: Median of 4.8 years
Outcome Trandolapril Placebo Comparisons
Primary outcome 21.9% 22.5% HR 0.96, 95%CI [0.88 - 1.06], p=0.43
Overall mortality 7.2% 8.1% RR 0.89, 95%CI [0.76 - 1.04], p=0.13
Nonfatal myocardial infarction 5.3% 5.3% RR 1.0, 95%CI [0.83 - 1.20], p=1.00
Decrease in BP from baseline at 36 months (mmHg) 4.4/3.6 1.4/2.4 p<0.001
Cough 39.1% 27.5% p<0.01
Syncope 4.8% 3.9% p=0.04
Drug discontinuation due to side effects 14.4% 6.5% p<0.001
  • At 3 years, 8.3% of patients in the placebo group were taking an open-label ACE inhibitor

Findings: In patients with stable coronary heart disease and preserved left ventricular function who are receiving "current standard" therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization.
ALLHAT study - Chlorthalidone vs Lisinopril vs Amlodipine for CVD, JAMA (2002) [PubMed abstract]
  • The ALLHAT study enrolled 33,357 patients with hypertension and either a history of CVD or risk factors for CVD
Main inclusion criteria
  • Age > 55 years
  • SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
  • One of the following: previous MI or stroke, left ventricular hypertrophy (LVH), type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
  • History of hospitalized or treated symptomatic heart failure
  • EF < 35%
Baseline characteristics
  • Average age 67 years
  • Women - 47%
  • Average BP - 146/84
  • Receiving treatment for hypertension - 90%
  • Race: White - 47% | Black - 32% | Hispanic - 16%
  • Qualifying risk factor: CVD - 52% | Diabetes - 36% | Smoker - 22% | LVH - 21% | Low HDL - 12%
Randomized treatment groups
  • Group 1 (15,255 patients) - Chlorthalidone 12.5 - 25 mg a day
  • Group 2 (9048 patients) - Amlodipine 2.5 - 10 mg/day
  • Group 3 (9054 patients) - Lisinopril 10 - 40 mg/day
  • Treatment was titrated to a BP goal of < 140/90
  • If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25-100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
  • There was another arm of the study that used doxazosin. That arm was stopped early due to an increased risk of major CVD events. See ALLHAT doxazosin for more.
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results

Duration: Average of 4.9 years
Outcome Chlorthalidone Amlodipine Lisinopril Comparisons
Primary outcome (6-year rate) 11.5% 11.3% 11.4% 1 vs 2 p=0.65 | 1 vs 3 p=0.81
Overall mortality (6-year rate) 17.3% 16.8% 17.2% 1 vs 2 p=0.20 | 1 vs 3 p=0.90
Stroke (6-year rate) 5.6% 5.4% 6.3% 1 vs 2 p=0.28 | 1 vs 3 p=0.02
Heart failure (6-year rate) 7.7% 10% 8.7% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Achieved BP goal (< 140/90) at 1 year 57.8% 55.2% 50.6% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Potassium < 3.5 mEq/L at 2 years 12.7% 2.6% 1.5% 1 vs 2 p<0.001 | 1 vs 3 p<0.001
New-onset diabetes at 4 years 11.6% 9.8% 8.1% 1 vs 2 p=0.04 | 1 vs 3 p<0.001

Findings: Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.





CSG Study - Captopril vs Placebo in the Treatment of Diabetic Kidney Disease, NEJM (1993) [PubMed abstract]
  • The CSG study enrolled 409 type 1 diabetics with proteinuria (≥ 500 mg/day)
Main inclusion criteria
  • Age 18 - 49 years
  • Type 1 diabetes for at least 7 years
  • Diabetic retinopathy
  • Urinary protein excretion ≥ 500 mg/day
  • Serum creatinine ≤ 2.5 mg/dl
Main exclusion criteria
  • NYHA class III or IV heart failure
  • Potassium ≥ 6 mEq/L
Baseline characteristics
  • Average age 35 years
  • Average BP 138/85
  • Average A1C - 11.7%
  • Average serum creatinine 1.3 mg/dl
  • Average 24-hour urinary protein - 2750 mg/day
Randomized treatment groups
  • Group 1 (207 patients) - Captopril 25 mg three times a day
  • Group 2 (202 patients) - Placebo
  • Patients were treated to a target BP of 140/90
  • Other classes of BP meds were allowed except for ACE inhibitors and calcium channel blockers
Primary outcome: Doubling of the baseline serum creatinine concentration to at least 2 mg/dl
Results

Duration: Median of 3 years
Outcome Captopril Placebo Comparisons
Primary outcome 12% 21% RR 0.57, 95%CI [0.35 - 0.94], p=0.007
Composite of death, dialysis, or kidney transplant 11% 21% RR 0.54, 95%CI [0.32 - 0.90], p=0.006
Drug discontinuation 16% 9% p=0.10
  • The captopril group had a lower average blood pressure throughout the study by about 2 mmHg

Findings: Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone
BENEDICT Study - Trandolapril vs Trandolapril/Verapamil vs Verapamil vs Placebo for Prevention of Diabetic Kidney Disease, NEJM (2004) [PubMed abstract]
  • The BENEDICT trial enrolled 1204 diabetics with hypertension and normoalbuminuria
Main inclusion criteria
  • Age ≥ 40 years
  • Type 2 diabetes
  • Taking hypertension meds or SBP ≥ 130 or DBP ≥ 85
  • Urinary albumin excretion < 20 mcg/min
  • Serum creatinine ≤ 1.5 mg/dl
Main exclusion criteria
  • HgA1C ≥ 11%
  • Nondiabetic kidney disease
Baseline characteristics
  • Average age 62 years
  • Average duration of diabetes - 7.9 years
  • Average A1C - 5.8%
  • Average BP - 150/87
  • Average serum creatinine - 0.9 mg/dl
  • Average urinary albumin excretion - 5.5 mcg/min
Randomized treatment groups
  • Group 1 (301 patients) - Trandolapril 2 mg once daily
  • Group 2 (300 patients) - Trandolapril 2 mg + verapamil sustained-release 180 mg per day
  • Group 3 (303 patients) - Verapamil sustained-release 240 mg per day
  • Group 4 (300 patients) - Placebo
  • There was a washout period of 3 - 6 weeks before randomization where calcium channel blockers and RAS inhibitors were discontinued
  • Patients were treated to a target BP of 120/80. Additional meds were allowed if needed in the following order: step 1 - HCTZ or furosemide; step 2 - doxazosin, prazosin, clonidine, methyldopa, or beta-blockers; step 3 - minoxidil or long-acting dihydropyridine calcium channel blockers
Primary outcome: Development of persistent microalbuminuria (overnight albumin excretion ≥ 20 μg per minute at two consecutive visits)
Results

Duration: Median of 3.6 years
Outcome Trandolapril Tran/Vera Verapamil Placebo Comparisons
Primary outcome 6% 5.7% 11.9% 10% 1 vs 4 p=0.01 | 2 vs 4 p=0.01 | 3 vs 4 p=0.54
Average BP during study 139/81 139/80 141/82 142/83 1 vs 4 p≤0.002 | 2 vs 4 p≤0.002 | 3 vs 4 p>0.05

Findings: In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.






Benazepril vs Placebo in Nondiabetic Kidney Disease, NEJM (2006) [PubMed abstract]
  • The study enrolled 224 patients with nondiabetic chronic renal insufficiency
Main inclusion criteria
  • Serum creatinine 3.1 - 5 mg/dl and CrCl of 20 - 70 ml/min
  • Nondiabetic kidney disease
  • Persistent proteinuria defined as ≥ 300 mg/day for ≥ 3 months
Main exclusion criteria
  • Diabetes
  • ACE or ARB therapy within past 6 weeks
  • NYHA class III or IV heart failure
  • Treatment with steroids, NSAIDs, or immunosuppressants
  • Renovascular disease
  • Cardiovascular event within 1 year
Baseline characteristics
  • Average age 45 years
  • Average BP 152/85
  • Average serum creatinine 4.0 mg/dl
  • Average CrCl - 27 ml/min
  • Average urinary protein excretion - 1.65 grams/day
  • Average potassium - 4.55 mEq/L
  • Kidney disease type: Glomerular - 61% | Hypertension - 17% | Polycystic kidneys - 11% | Interstitial - 4%
Randomized treatment groups
  • Group 1 (207 patients) - Benazepril 10 mg twice a day
  • Group 2 (202 patients) - Placebo twice a day
  • Before randomization, all eligible patients underwent an 8-week run-in phase where tolerability of benazepril therapy had to be demonstrated
  • Other blood pressure medications excluding ACE inhibitors and ARBs were permitted. Patients were treated to a target BP of 130/80.
Primary outcome: Composite of doubling of the serum creatinine level, end-stage renal disease, or death
Results

Duration: Average of 3.4 years
Outcome Benazepril Placebo Comparisons
Primary outcome 41% 60% p=0.004
Median rate of decline in GFR 6.8 ml/min/year 8.8 ml/min/year p=0.006
  • Doubling of the serum creatinine was significantly lower in the benazepril group than in the placebo group (p=0.02)
  • The incidence of end-stage renal disease was significantly lower in the benazepril group than in the placebo group (p=0.02)
  • The incidence of adverse events was similar between the 2 groups. (Patients who could not tolerate benazepril were excluded during the run-in phase)

Findings: Benazepril conferred substantial renal benefits in patients without diabetes who had advanced renal insufficiency





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