ACE Inhibitors or ARBs in Hypertension and/or Chronic Kidney Disease?

A pair of articles in the January 1, 2008 Annals of Internal Medicine brings together the existing literature to address issues that have persisted since the introduction of angiotensin-receptor blockers (ARBs): namely, when and how these drugs might be advantageous in conditions long served by angiotensin-converting enzyme (ACE) inhibitors.

A meticulous survey of studies found that the two drug classes are about equally safe and effective at managing high blood pressure and have similar effects on other risk factors and clinical outcomes in patients with essential hypertension. It also confirmed that ARBs are less likely to cause coughing, but suggested that the side effect might be less common with ACE inhibitors than randomized trials indicate.

In the setting of chronic kidney disease (CKD), concludes the other study, which is a meta-analysis, ACE inhibitor and ARB monotherapy are similarly effective at reducing proteinuria, but a combination of the two angiotensin-2-suppressing drugs works better than either agent individually. But a blanket recommendation to combine them would be premature, according to the authors, because there is little evidence that the combination would improve clinical outcomes over monotherapy, and the safety of such combination therapy is largely undefined.

Study Highlights

• Essential hypertension
  
  • Included were studies that directly compared ACE inhibitors and ARBs of any design (RCTs, controlled trials, nonrandomized trials, cohort and case control studies) lasting at least 12 weeks and enrolling at least 20 patients, which provided direct comparison of ACE inhibitors and ARBs.
  • Outcomes examined were blood pressure control, adherence, quality of life, intermediate outcomes, and harms.
  • Of 61 studies analyzed, 47 were RCTs, 9 were retrospective cohort studies, 1 cross-sectional, 1 case control cohort, and 1 nonrandomized trial.
  • Rates of use as monotherapy were similar for the 2 classes of drugs.
  • ACE inhibitors and ARBs had similar efficacy for blood pressure control, with no significant differences in benefits or harms (strength of evidence: high).
  • Quality-of-life measures and adherence were similar for ACE inhibitors and ARBs.
  • There were no consistent differential effects seen for death and cardiovascular events.
  • Both classes of medication had similar effects on lipid levels, left ventricular mass, and risk for dysglycemia or renal dysfunction.
  • Adverse effects of headache and dizziness were similar for the 2 classes.
  • Cough as an adverse effect was 3 times more common with ACE inhibitors, with overall rates much higher in randomized trials (9.9% vs 3.2%) vs cohort-based studies (1.7% vs 0.6%).
  • The number needed to treat to cause 1 case of chronic cough for ACE inhibitors was 15.
  • The average duration of follow-up exceeded 6 months in only one third of the head-to-head studies, and there was a lack of long-term studies.
  • There was a lack of adequate studies reporting adverse effect profile of both medication classes.
• Chronic renal disease
  
  • Included were RCTs of short-term (1 to 4 months) and longer-term (5 to 12 months) studies involving a total of 6181 patients with microalbuminuria and proteinuria of diabetic origin and other causes and reported changes in proteinuria during follow-up.
  • Trials were at least 4 weeks in duration with parallel group or crossover designs.
  • Excluded were studies of patients who had renal transplantation and those with less than 10 participants.
  • Of 49 RCTs, 12 compared ARBs with placebo, 9 with calcium-channel blockers, 23 with ACE inhibitors, and 16 with the combination of ACE inhibitors and ARBs.
  • 23 trials compared combination ARBs and ACE inhibitors with an ACE inhibitor alone.
  • Monotherapy with ACE inhibitors or ARBs reduced proteinuria to a similar degree but less than combination therapy.
  • Mean reduction in proteinuria with combination vs ARB monotherapy in 5- to 12-month studies was 0.75 vs 0.82 (ratio of means) with ACE inhibitors.
  • Monotherapy with ARBs reduced proteinuria vs placebo, with a ratio of means of 0.57 in 1 to 4 months and 0.69 in 5 to 12 months.
  • Results were similar for ACE inhibitors and ARBs vs calcium-channel blockers.
  • 92% of studies lacked quantitative data on adverse drug reactions.
  • In the absence of safety data on long-term combination therapy with ACE inhibitors and ARBs, therapy should be limited to those with stage 3 or 4 disease with close monitoring of potassium levels.
  • The editorialist concluded that monotherapy with ACE inhibitors or ARBs was sufficient treatment for early-stage renal disease with relatively low albumin exertion, and combination therapy was effective for patients with heavier proteinuria when monotherapy failed to decrease 24-hour urinary protein excretion to less than 0.5 g.

Summary

• ACE inhibitors and ARBs are equivalent in efficacy for the treatment of essential hypertension, and ACE inhibitors are associated with a 3 times higher rate of chronic cough.
• ACE inhibitors and ARBs are similar in efficacy for the treatment of proteinuria of chronic renal disease, with the combination being more effective than monotherapy with either drug, but long-term adverse effects are not well documented.

Sources:

Sources

1. Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008;148:16-29.
2. Kunz R, Friedrich C, Wolbers M, Mann JFE. Meta-analysis: Effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30-48.
3. Steve Stiles, Désirée Lie. ACE Inhibitors or ARBs in Hypertension? In Chronic Kidney Disease? Medscape Medical News, Medscape Internal Medicine. January 17, 2008; Reviewed and Renewed: February 13, 2009
   
   

Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension

With the popularity of ACE inhibitors in mind, investigators conducted a systematic review of published studies to determine how effective the drugs actually are in reducing blood pressure. They also examined dose effectiveness, adverse effects, and the role of co-occurring conditions.

The Study Findings

Researchers looked for double-blind studies comparing ACE inhibitors and placebo. All included studies were at least 3 weeks in duration and measured blood pressure as an endpoint at 3-12 weeks. Studies that featured a response-dependent titration of medications were included in the review. Only research that focused on patients with a blood pressure above 140/90 mm Hg was reviewed.

The review included 92 trials with a total of 12,954 participants (mean age, 54 years). Mean baseline blood pressure was 157/101 mm Hg and mean pulse pressure was 56 mm Hg. The majority (75%) of included studies was industry-sponsored, and 82% of the trials examined fixed-dose ACE inhibitors. The duration of trials was generally short, which limited data with regard to adverse events and study withdrawals.

The main potential source of bias in the research was a lack of information with regard to how the studies were blinded. In addition, the reviewers suggested that the researchers could have preferentially selected patients more likely to respond to ACE inhibitors. This selection bias could make ACE inhibitors appear more effective than they truly are.

The studies covered 14 ACE inhibitors. The degree of homogeneity with regard to their efficacy in reducing blood pressure was remarkable. No one medication appeared superior to others.

Overall, ACE inhibitors had a modest collective effect in reducing blood pressure. The mean reduction in systolic blood pressure ranged between 6 mm Hg and 9 mm Hg, and the mean reduction in diastolic blood pressure was 4-5 mm Hg. Less data were available with regard to the blood pressure effects of ACE inhibitors at 1-12 hours after dosing, but the average decrease in blood pressure with ACE inhibitors around their peak concentration was greater than their average efficacy (11.4/6.4 mm Hg).

Dose Effectiveness

The study provided some important information about the relationship between the dose of ACE inhibitors and their effect on blood pressure. Doses lower than the manufacturers' maximum recommended dosage had the same blood pressure-lowering effect as the maximum dose. For example, doses of one eighth to one quarter of the maximum achieved the blood pressure-lowering effect of the maximum dose in 60% to 70% of cases. Half of the maximum dose achieved it 90% of the time. There was no blood pressure-lowering effect at or below one sixteenth of the maximum suggested dose. These data suggest that use of the maximum dosage of ACE inhibitors to achieve greater blood pressure control is usually unnecessary.

The research also identified dosing information for individual ACE inhibitors and suggested that the manufacturers' recommended starting doses of benazepril, moexipril, and ramipril are higher than the minimum dose needed to reduce blood pressure. Conversely, captopril did not appear effective in reducing blood pressure at the manufacturers' recommended starting dose. Most of the maximum blood pressure-lowering effect of lisinopril was achieved at only one eighth of the recommended maximum dose.

ACE inhibitor dosing was also one of the biggest deficits in the current review. It was clear to the review authors that not all data in regard to the efficacy of different doses of ACE inhibitors were published. Instead, the data were supplied to regulators privately to determine the appropriate dosing range of ACE inhibitors.

Only half of trials provided data in regard to the rate of withdrawal due to adverse events. Collectively, there was no difference between ACE inhibitors and placebo in this critical outcome. ACE inhibitors did not significantly affect patients' heart rate.

Addressing Other Health Issues

Physicians might choose ACE inhibitors to treat hypertension for other possible health benefits associated with these medications, especially the potential to prevent type 2 diabetes. ACE inhibitors can have a positive effect on glucose metabolism through multiple mechanisms, and previous research suggested that they could prevent incident diabetes compared with other antihypertensive medications. Specifically, the Captopril Prevention Project demonstrated a 14% relative reduction in this outcome among participants receiving captopril vs a diuretic or beta-blocker. This benefit, associated with captopril, was evident regardless of the baseline risk for diabetes, although the incidence of diabetes was not a primary outcome of the study.

The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial directly examined the effect of ramipril vs placebo on the incidence of diabetes. This study examined patients with impaired fasting glucose levels or reduced insulin sensitivity but no history of cardiovascular disease. After a median of 3 years of treatment, ramipril was not associated with a significantly lower incidence of diabetes compared with placebo. Median fasting plasma glucose levels were also similar at the end of the trial. However, ramipril was associated with a higher rate of return to normoglycemia.

Physicians might also consider using ACE inhibitors for hypertension in order to prevent incident heart failure. However, although ACE inhibitors are associated with numerous positive outcomes, including reduced mortality, among patients with known heart failure, little evidence exists that they provide special protection against new heart failure. In a study of quinapril and placebo initiated shortly after myocardial infarction, there was no difference between treatment groups in a composite outcome of cardiovascular death and significant cardiovascular events. Specifically, no difference was found in the risk for heart failure among those patients at high cardiovascular risk. Similarly, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Hearth Attack Trial (ALLHAT), the incidence of heart failure was similar among patients receiving lisinopril and chlorthalidone.

Commentary

Although ACE inhibitors may not provide special protection against diabetes or heart failure among patients with hypertension, physicians should still consider these medications when managing hypertension. In fact, the nature of hypertension management dictates that they have to because most patients require more than 1 medication initially. In a recent study of men receiving care at a Veteran Affairs hospital, 60.4% of subjects with hypertension and significant cardiovascular risk were receiving multiple antihypertensive medications. Nevertheless, only 28% of these same patients had reached their goal blood pressure levels, indicating that they needed titration of their medications, if not the addition of other antihypertensive drugs.

Authors' conclusions

There are no clinically meaningful BP lowering differences between different ACE inhibitors. The BP lowering effect of ACE inhibitors is modest; the magnitude of trough BP lowering at one-half the manufacturers' maximum recommended dose and above is -8/-5 mm Hg. Furthermore, 60 to 70% of this trough BP lowering effect occurs with recommended starting doses. The review did not provide a good estimate of the incidence of harms associated with ACE inhibitors because of the short duration of the trials and the lack of reporting of adverse effects in many of the trials.

Clinical Pearls

• In the current review, ACE inhibitors were associated with an average reduction in systolic blood pressure between 6 mm Hg and 9 mm Hg and in diastolic blood pressure of 4-5 mm Hg;
  
  
• ACE inhibitors achieved most of their power in reducing blood pressure at half of the maximum recommended dose, or less;
  
  
• ARBs provide similar reductions in blood pressure compared with ACE inhibitors; and
  
  
• There is no strong evidence that ACE inhibitors can prevent incident diabetes mellitus or heart failure.

Sources: Medscape Family Medicine Best Evidence Review
Cochrane Database Syst Rev. 2008; (4):CD003823 (ISSN: 1469-493X)
Full text at Cochrane Library

caution against combining the 2 classes of RAS inhibitors

The updated recommendation is based on the results of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), an international study supported by Boehringer Ingelheim, the Heart and Stroke Foundation of Ontario, and the Canadian Institutes of Health Research. The main results of ONTARGET, published in 2008,^[9] showed that in 25,620 patients with vascular disease or type 2 diabetes, the combination therapy had a greater blood pressure-lowering effect than either telmisartan or ramipril alone, but it did not produce any additional benefit in terms of patient outcomes, and it was associated with more side effects, such as hyperkalemia, hypotension, and renal impairment. The guidelines also note that in patients with stage 3 chronic kidney disease (glomerular filtration rate > 30 mL/min) the ACE inhibitor plus ARB combination reduced urine protein but did not reduce cardiovascular outcomes, and it worsened renal outcomes, including the need for acute dialysis compared with the ACE inhibitor alone.

The only data to support improved patient outcomes with the combination of an ACE inhibitor plus an ARB are in people with heart failure, where, the guidelines note, the combination reduces recurrent hospitalization. Hence, the guidelines advise that the use of combination of ACE inhibitor with an ARB therapy should only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy. They advise that for people already on the combination and stable, physicians should consider that prescribing 1 of the 2 drug classes alone will reduce cardiovascular events to the same extent and that other therapeutic regimens have the potential to reduce cardiovascular events and blood pressure to a greater degree. Trials are ongoing of a combination of an ACE inhibitor with an ARB in people with chronic kidney disease and diabetes.