Angiotensin converting enzyme (ACE) inhibitors are an excellent family of anti-hypertensive medications.  Captopril (Capoten), the oldest and best researched, is available as a very inexpensive generic.  One study found that older individuals had less cognitive deterioration on captopril, which was attributed to the fact that it is brain-penetrating, while enalapril and others are not.  However, one study is not enough to use for a practice decision.  It costs only $3-6 per month wholesale for 50-100 mg twice a day

Enalapril (Vasotec) is longer acting, allowing once a day dosing, and also very inexpensive.  Lisinopril (Prinivil), ramipril, perindopril, fosinopril, quinapril, and benazepril (Lotensin) are other ACE inhibitors but a somewhat more expensive.  All are probably equally good, although one study suggested advantages to perindopril and ramipril after a heart attach.  Besides lowering blood pressure, ACE inhibitors protect the kidney, lower stroke and heart attack risk, and help the patient live longer. 

Doctors often give up on ACE inhibitors if patients develop an annoying cough.  However, for some patients, the cough can be eliminated simply by taking an iron replacement, which appears a safe strategy, especially for women who tend to be lower in iron than men.  For men, I would check the iron status first.  

I like ACE inhibitors as my first line anti-hypertensive and use captopril or enalapril.  If an ACE inhibitor is not enough, I add hydrochlorothiazine, a diuretic.  However, I follow many non-medicine interventions to prevent and hold down high blood pressure and have also used CoQ10 and melatonin for the anti-hypertensive values along with medications.

ACE Inhibitors Better Than ARBs: In doing a meta-analysis of all relevant published studies (1966-August 2004), researchers concluded that ACE inhibitors have been definitively shown to prevent death. However, studies with ARBs in similar populations have not reduced death or heart attacks. Angiotensin Receptor Blockers versus ACE Inhibitors: Prevention of Death and Myocardial Infarction in High-Risk Populations. Epstein BJ, Gums JG. University of Florida, Gainesville, FL. Ann Pharmacother. 2005 Mar;39(3):470-80.

ACE-Inhibitor Identical Results with ARB for High Blood Pressure Control: In a 16-week DB PC study of 1213 adults with mild to severe hypertenion, the angiotensin II receptor blocker valsartan 160 mg/day vs. lisinopril 20-mg/day for 4 weeks. Responders continued monotherapy, whereas nonresponders had hydrochlorothiazide 12.5 mg added for the final 12 weeks. 8.4% treated with valsartan vs. 1.2% treated with lisinopril withdrew. Valsartan- and lisinopril-based treatments were similarly effective with mean SBP/DBP reductions of 31.2/15.9 mm Hg and 31.4/15.9 mm Hg. BP was controlled in 82.7% of valsartan vs. 81.6% on lisinopril. AEs were experienced by 5.1% of the patients treated with valsartan and 10.7% of those treated with lisinopril (P=.0001), with dry cough observed in 1.0% and 7.2% of patients, respectively (P<0.001). Comparison of valsartan 160 mg with lisinopril 20 mg, given as monotherapy or in combination with a diuretic, for the treatment of hypertension: the Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril (PREVAIL) study. Malacco E, Santonastaso M, Vari NA, Gargiulo A, Spagnuolo V, Bertocchi F, Palatini P; Blood Pressure Reduction and Tolerability of Valsartan in Comparison with Lisinopril Study. University of Milan, Italy. Clin Ther. 2004 Jun;26(6):855-65 Ed: Angiotensin II receptor blockers are much more expensive. The best ACE inhibitor is enalapril which costs only $2-4/month.

Doubling ACE Inhibitor as Good as Adding ARB in DM:  In a 12-month DB PC study of adult diabetics with high blood pressure using either lisinopril 40 mg once daily or dual-blockade treatment with candesartan 16 mg once daily and lisinopril 20 mg once daily, no significant difference was found between dual-blockade and lisinopril 40 mg once daily (P = 0.10). Long-Term Dual Blockade With Candesartan and Lisinopril in Hypertensive Patients With Diabetes: The CALM II study. Andersen NH, Poulsen PL, et al. Aarhus University Hospital, Denmark. Diabetes Care. 2005 Feb;28(2):273-277

ACE Inhibitors Better Than Angiotensin II Receptor Blockers (ARB) for Diabetics: From Medline, Embase, the Cochrane controlled trials register, conference proceedings, and contact with investigators, 36 of 43 identified trials compared ACE inhibitors with placebo (4,008 patients), four compared ARBs with placebo (3331 patients), and three compared ACE inhibitors with ARBs (206 patients). ACE inhibitors significantly reduced all cause mortality (relative risk 0.79) compared with placebo but ARBs did not (0.99), although baseline mortality was similar in the trials. Both agents had similar effects on renal outcomes. Reliable estimates of the unconfounded relative effects of ACE inhibitors compared with ARBs could not be obtained owing to small sample sizes. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ  10/9/2004;329:828. 

Low Dose Captopril and Losartan Synergistic HBP Effect: Am J Hypertens. 2002 Nov;15(11):1003-5. High dose combo is less than additive but low dose more than additive. Losartan AT(angiotensin)(1) receptor blocker.

ACE Inhibitors Very Inexpensive: Cheapest generic captopril $3-$11/mo given 25-150 BID-TID or enalapril (Vasotec) $3 for 10 mg once a day. Others: benazepril (Lotensin), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), quinapril (Accupril), ramipril (Altace), trandolopril (Mavik). These others cost $16-32/mo.

Atrial Fibrillation: Stroke Prevented by ACE Inhibitor: In a DB PC study of 476 patients with atrial fibrillation, the risk of a major stroke decreased 41% in patients who already were on anticoagulants, and 34% in patients who were not. Patients with atrial fibrillation obtain substantial additional benefit from anticoagulant therapy. Dr. John C. Chalmers, et al. George Institute for International Health, Sydney, Australia. Stroke 9/1/05.

Heart: ACE Inhibitor Better Than Diuretic Preventing Male Heart Attacks in Australian 2003 Study: Researcers found that ACE inhibitors are somewhat better at preventing heart attacks, at least in men in a 4-year study of 6,083 people ages 65-84. Half were randomly assigned to get a diuretic, the other half an ACE inhibitor as their first treatment. Hydrochlorothiazide and the ACE inhibitor enalapril were recommended, but each patient's doctor chose drug and dose. Drugs in any of three other groups -- beta blockers, calcium channel blockers, and alpha blockers -- could be added to bring blood pressure down. ACE inhibitor group had 11 percent fewer deaths and "cardiovascular events" such as heart attacks or strokes. But the greater benefit was entirely among the men. Africans, who get less benefit than Europeans from ACE inhibitors but often do very well on diuretics, made up 35% of the U.S. study. Ninety-five percent of the people in the Australian study were European. NEJM 2/13/03

ACE Inhibitors Favored in Large Review: ACE inhibitors decrease stroke and other cardiovascular events by 20% to 30% compared with placebo among patients at high cardiovascular risk, according to a review of 15 randomized trials. They are safer or more effective than diuretics and beta-blockers, the first-line treatments recommended by national hypertension guidelines. The Blood Pressure Treatment Trialists’ Collaboration evaluated placebo-controlled studies, which collectively followed nearly 75,000 people. Lancet. 2000;356:1942-3, 1949-54, 1955-64. 

ACE Inhibitor Lowers Stroke and Heart Attack in CVD Patients: In the DB PC Hope study of 9,000 patients with coronary disease, stroke or peripheral vascular disease, researchers found 25% reductions in heart attacks, stroke, and cardiovascular death. Benefit 75-325 mg aspirin about same. Warfarin a benefit with fibrillation. Carotid endarterctomy only for severe stenosis over 70%. BMJ 12/9/01

ACE Inhibitor Treats HBP in Blacks Better: ACE inhibitor ramipril and amlodipine, a calcium channel blocker were compared in a DB study. While both drugs were equally effective at controlling blood pressure, patients who took the ACE inhibitor had a 48 percent lower risk of death, dialysis and dangerous drops in kidney function over three years; they also had a 36 percent slower decline in kidney function. Calcium channel blockers have been recommended in the past for blacks with kidney damage, an event that is 20 times more common in blacks. Case Western, JAMA 6/9/01

ACE Inhibitor Helps in SAVE Study: The Survival and Ventricular Enlargement study of 2,231 adults ages 21-79 following heart attacks without HBP treatment used up to 50 t.i.d. of captopril for 3.5 years and found that 22% fewer developed heart failure with a 19% reduction in mortality.

ACE Inhibitor Reduces Strokes & Heart Attacks, Increases Longevity: The 12,000 heart patient European trial on Reduction of Cardiac Events (Europa study) DB PC using 8 mg perindopril in addition to their existing medication, such as aspirin, statins and beta-blockers, for an average of four years. Risk of death was cut by 11%, 24% reduction in heart attacks and a 39% reduction in heart failure cases in the patients living with stable heart disease. The risk reduction was seen in all patient groups, whether or not they had conditions such as high blood pressure or diabetes, and irrespective of age. An early report from the study noted reduced strokes. 8/30/03

ACE Inhibitor Reduces Cardiovascular and Renal Events in Microalbuminuria: Treating microalbuminuria with an angiotensin-converting enzyme (ACE) inhibitor in the absence of either hypertension or hypercholesterolemia can reduce cardiovascular and renal events by 44% over a four-year period. Subjects randomized to the ACE inhibitor, fosinopril, experienced a 23% decrease in urinary albumin excretion (P < .001). Pravastatin did not reduce urinary albumin excretion rates and achieved a 25% nonsignificant reduction in cardiovascular and renal events. Weik H. van Gilst, University of Groningen, the Netherlands. Prevention of Renal Vascular End-Stage Disease Intervention Trial (PREVEND IT). Microalbuminuria is often overlooked or considered only minimally significant by many clinicians, and that the study results suggest a more aggressive approach to treatment of the condition is needed. Microalbuminuria is associated with an increased cardiovascular and renal risk, treating these patients might impact survival. PREVEND IT a DB PC 2 x 2 factorial design that randomized 854 patients to fosinopril 20 mg or placebo and pravastatin 40 mg or matching placebo. The mean follow-up was 46 months and the primary endpoint was a composite of cardiovascular mortality, hospitalization for cardiovascular morbidity or end-stage renal disease. The average age of patients was 51 ± 12 years and 65% were men. More than 3% had experienced a prior cardiovascular event and nearly 5% had previously used at least one cardiovascular agent. The median urinary albumin excretion rate was 22.9 mg/24h with a range of 25.8 to 41.8 mg/24h. AHA 2003 Scientific Sessions: Late-Breaking Clinical Trials. Nov. 12, 2003.

ACE Inhibitor Captopril: Helps Exercise Tolerance, Scleroderma: Increases exercise tolerance in stable angina (Clin Exp Obstet Gynecol. 2003;30(1):43-); reduces experimental myosin-induced auto-immune myocarditis in rats; helps Chagas disease myocarditis (Circulation. 2003 May 6;107(17):2264-9); sublingual captopril better than nifedipine in hypertensive crisis (Blood Press. 2003;12(1):46-8); helps with scleroderma renal crisis (J Clin Hypertens (Greenwich). 2003 Mar-Apr;5(2):168-70, 176); HCT, but not captopril, raised tHcy by 16% (P =.003) and also creatinine and cystatin C (P =.025 and P =.004, respectively). (Metabolism. 2003 Mar;52(3):261-3); In DB x 1 year, helped protect kidney function s/p myocardial infarct. Eur Heart J. 2003 Mar;24(5):412-20; vasopeptidase inhibitor omapatrilat, a drug which causes simultaneous inhibition of both angiotensin converting enzyme and neutral endopeptidase better than captopril at preventing adverse myocardial apotosis and remodeling in rats s/u infarction. Cardiovasc Res. 2003 Mar;57(3):727-37; DB primary end point was all-cause mortality and there were 499 (18%) and 447 (16%) deaths in the losartan and captopril group, respectively (p = 0.07). More cardiovascular deaths with losartan (420, 15%) than with captopril (363, 13%; p = 0.03). Losartan was better tolerated than captopril with fewer patients discontinuing medication (17% versus 23% for losartan and captopril, respectively). In conclusion, if tolerated, captopril should remain the preferred treatment for patients after complicated acute myocardial infarction. Expert Opin Pharmacother. 2003 Mar;4(3):407-9; Captopril helped HBP and erectile dysfunction in hypertensive rats. Int J Impot Res. 2002 Dec;14(6):494-7

ACE Inhibitor Captopril May Be Better at Preventing Cognitive Deterioration: In a 1-year Japanese random assignment study of 162 patients with cognitive impairment and high blood pressure, those treated with brain-penetrating ACE inhibitors captopril or perindopril had only a 0.6 decline in their MMSE score vs. a 4.6 point decline with non-penetrating ACE inhibitors enalapril or imidapril and a 4.9 point decline with calcium channel blockers. Blood pressure was lowered to the normal range equally well with all the medications. Tokohu University, Neurol 10/2004. Ed: This study was not blinded, so needs to be repeated with more patients using a double-blind design. Captopril is very inexpensive costing about $3 per month (50 mg b.i.d.) wholesale and $13 per month retail. Perindopril (Aceon) is not available in the U.S. and costs $20 per month from Canada. 

ACE Inhibitor Reduces Muscle Loss: Wake Forest University studied 641 older women with hypertension (Lancet 2002;359:926-30). Participants who took the drug continually had a significantly lower average decline in muscle strength over three years, compared with continual, intermittent users of other antihypertensive drugs and participants who took no antihypertensives. The average decline in walking speed was 10 times lower! The drugs improve muscle efficiency by changing a protein in muscle cells that makes the muscles more resistant to fatigue, increasing blood flow and reducing inflammation and consequent wasting of muscle.

Iron Supplement Helps ACE Inhibitor Cough: DB PC showed major decrease in ACEI cough in those getting the side-effect with 256 mg iron QD x 4 weeks. Iron supplementation inhibits cough associated with ACE inhibitors. Lee SC, Park SW, Kim DK, Lee SH, Hong KP. Hypertension. 2001 Aug;38(2):166-70, Seoul. Ed: Excessive iron has been debated as to its harmful effects for older individuals. I would hesitate to recommend iron supplementation unless the cough was a real problem or the patient was deficient in iron.

Increasing ACE-Inhibitor Almost as Good as Adding Angiotensin Receptor Blocker: The two DB AMAZE studies sponsored by AstraZeneca, maker of ARB candesartan, of 1096 hypertensive patients who were uncontrolled on ACE-Inhibitor lisinopril 20 mg daily were randomized (1:1) to receive either 8 weeks of high-dose lisinopril (40 mg) or the addition of candesartan (16 mg) for 2 weeks followed by 32 mg for 6 weeks. The studies demonstrated decreases in trough sitting systolic/diastolic blood pressures at Week 8 of 7.5/6.1 mm Hg for the lisinopril up-titration treatment group vs. 10.5/7.8 mm Hg for the lisinopril plus candesartan treatment group. The blood pressure control rates (<140/<90 mm Hg) were 36.9% and 42.7%. Both treatment regimens were well tolerated. For hypertensive patients not controlled by lisinopril 20 mg once daily, addition of candesartan (32 mg once daily) or doubling the dose of lisinopril provides safe, additional reduction of blood pressure. Antihypertensive Efficacy of Candesartan-Lisinopril in Combination vs. Up-Titration of Lisinopril: The AMAZE Trials. Izzo JL Jr, Weinberg MS, Hainer JW, Kerkering J, Tou CK. Buffalo. J Clin Hypertens (Greenwich). 2004 Sep;6(9):485-93

Higher Dose ACE Inhibitor Better for Heart Failure: In 2-year follow-up of 298 adults with mild to moderate heart failure, worsening was observed for 31.5% on captopril 25 mg twice a day vs. 22.4% on 50 mg twice a day (p = 0.088). The higher dose showed fewer hospitalizations (22.4 to 14.5% (p = 0.1)) and fewer fatal and nonfatal cardiac events (22% (p = 0.142)). Dizziness and hypotension were a little more frequently reported in the high-dose group. Serum creatinine values showed no significant changes. Long-term effects of clinical outcome with low and high dose in the Captopril in Heart Insufficient Patients Study (CHIPS). Clement DL, De Buyzere M, et al. Gent, Belgium. Acta Cardiol. 2000 Feb;55(1):1-7.

Higher Dose ACE Inhibitor Fewer Heart Transplant Deaths: In a study of 237 heart transplantation candidates, those who, for whatever reason, received ACE-inhibitors below the recommended dosages (<75 mg captopril, 20 mg enalapril, 20 mg lisinopril, 5 mg ramipril/day), had an increased mortality risk (25% vs. 16%) and was the strongest predictor of mortality. ACE inhibitor dosage at the time of listing predicts survival. Berger R, Kuchling G, et al. University of Vienna, J Heart Lung Transplant. 2000 Feb;19(2):127-33

Heart: Perindopril, Ramipril Did a Little Better After Heart Attack: In a retrospective cohort study of 18,453 patients over age 64 admitted for an acute myocardial infarction, 7512 patients who filled a prescription for an ACE inhibitor within 30 days of discharge and who continued to receive the same drug for at least 1 year. Enalapril, fosinopril, captopril, quinapril, and lisinopril were associated with higher mortality than was ramipril; the adjusted hazard ratios were 1.47, 1.71, 1.56, 1.58, and 1.28, respectively. The adjusted hazard ratio associated with perindopril was 0.98. Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after acute myocardial infarction: a class effect? Pilote L, Abrahamowicz M, et al. McGill University, Montreal, Canada. Ann Intern Med. 2004 Jul 20;141(2):102-12.

Heart: Perindopril Helped After Heart Attack in Elderly: In a 1-year DB PC study of 1252 elderly, average age 73, after a heart attack, the ACE inhibitor reduced remodelling by 46% when compared to a placebo, according to a study presented at the European Society of Cardiology congress. Remodelling occurs when the heart adapts to injury caused during a heart attack. It results in enlargement of the organ and a change in its shape, causing it to pump blood less effectively. In the elderly, the heart typically deteriorates significantly over the following months after a heart attack leading to heart failure. There is a growing body of evidence suggesting that most patients should be put on ACE inhibitors following a heart attack. Roberto Ferrari, et al. University of Ferrara, Italy. European Society of Cardiology Congress 9/3/05.

Potassium: ACE Inhibitor Reduces Risk of Hypokalemia: In the 4.5 years HOPE study of 9297 adults at high cardiovascular risk, randomized to an ACE inhibitor or to placebo, 692 patients had a serum potassium level >5.0 mM and 137 with a serum potassium level <3.5 mM, defined as hyper- and hypokalemia, respectively. Serum potassium was measured 1 month after start of randomized treatment. With hyperkalemia, cardiovascular risk was unchanged compared to normokalemia (15.5 vs 15.7%, p > 0.4, respectively), with hypokalemia, risk was higher (22.6% vs 15.5%, respectively, p = 0.023). Ramipril reduced hypokalemia (1.15 vs 1.86% with placebo, p = 0.005), particularly in those participants on diuretics (3.8% vs 6.5%, p = 0.07). Serum potassium, cardiovascular risk, and effects of an ACE inhibitor: results of the HOPE study. Mann JF, et al. Ludwig Maximilians University, Munich, Germany. Clin Nephrol. 2005 Mar;63(3):181-7.

Sex Drive: ACE Inhibitors and Angiotensin II Blockers Better for Sex Drive: A study reports that for men diuretics, alpha-agonists and beta-blockers appear to affect sexual function more than calcium antagonists and ACE inhibitors. Angiotensin II antagonists may actually improve sexual function. A small study of 105 women found the beta-blocker atenolol impaired sexual desire and performance while the angiotensin II antagonist valsartan did not. Roberto Fogari Am J Hypertens 1/2004;14:77-81

Thomas E. Radecki, M.D., J.D.

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