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Sanders GD, Coeytaux R, Dolor RJ, et al. Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), and Direct Renin Inhibitors for Treating Essential Hypertension: An Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Jun. (Comparative Effectiveness Reviews, No. 34.)

Future Research

With the exception of rates of cough, the hypothesis that angiotensin-converting enzyme inhibitor(s) (ACEIs), angiotensin II receptor blocker(s)/antagonist(s) (ARBs), and direct renin inhibitors have clinically meaningful differences in long-term outcomes in individuals with essential hypertension is not strongly supported by the available evidence. Given the importance of these issues, it is notable how few large, long-term, head-to-head studies have been published.

Further comparative studies in this area should emphasize:

  • Subgroups of special importance such as individuals with essential hypertension and diabetes mellitus, congestive heart failure, chronic kidney disease, and dyslipidemia.
  • Pragmatic designs such as clinical trials in which treatment is consistent with typical clinical practice, or randomization by organizationally meaningful clusters, such as practice organizations or health plans.
  • Outcomes over several years, so that cardiovascular and cerebrovascular events can be compared between the three medication classes.
  • Outcomes measured according to current clinical standards.
  • Cancer-related outcomes, which are infrequently reported in the existing literature.
  • Broader representation of groups such as the elderly and ethnic and racial minorities.
  • Evaluation of differential effects of specific ACEIs or ARBs that are not shared by other agents within their respective medication class. (Only one direct renin inhibitor, aliskiren, is currently available.)
  • Long-term comparisons of direct renin inhibitors with ACEIs and ARBs.

In addition, we think that research aimed at generating additional evidence regarding four specific areas should be prioritized. These areas include:

  1. Relative persistence with drug therapy across the different classes of drugs.
    Comment: Although we report with moderate confidence that persistence with drug therapy is greater with ARB treatment than with ACEI treatment, the medication discontinuation rates varied significantly across studies. Because of the important benefit of remaining on these medications for the reduction of cardiovascular and cerebrovascular outcomes, differential medication persistence may have important health implications. In addition, medication discontinuation often requires followup visits and initiation of alternative medications and therefore has health economic ramifications as well. Future studies that more precisely estimate discontinuation rates in usual clinic settings, the additional health care utilization following discontinuation, and the conditional tolerability of an ACEI or ARB following prior intolerance to one of these agents would be valuable in understanding the consequences of differential medication discontinuation.
  2. Risk of new cancer diagnoses
    Comment: Recently, a review of ARBs found a small increased risk in new cancer diagnoses in patients treated with medications in this class.133 This link is putatively due to the role of the AT1 receptor in regulating cell proliferation. None of the large studies included in that review were included in the current review due to differences in the target population or in the comparator medications. None of our included studies reported cancer diagnosis or cancer death as an outcome, and our review was therefore unable to provide any further evidence supporting or refuting this hypothesis. Future research, either in large clinical trials with long term follow up or similar observational designs should examine this important outcome further.
  3. The potential to gain insight on the comparative benefits and harms of ACEIs, ARBs, and direct renin inhibitors based on findings from studies evaluating patients with other, related conditions such as congestive heart failure, ischemic heart disease, and chronic kidney disease.
    Comment: While our review is restricted to patients with essential hypertension, the agents studied here have been compared in large studies for related conditions such as congestive heart failure, ischemic heart disease, and chronic kidney disease. These systematic reviews have limited inclusion of studies to those conducted in patients with the target condition at the time of enrollment (i.e., hypertension, ischemic heart disease, congestive heart failure, or nephropathy); however, all have examined an overlapping set of efficacy and safety outcomes. As a result, important direct comparison trials are often excluded from reviews such as ours because they do not meet the target condition inclusion criteria. Such was the case of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), which was excluded from this review because no results were reported exclusively for patients with hypertension. This study provided the largest direct comparison of an ACEI versus an ARB with sufficient power to detect differences in cardiovascular events. As in our review, the ONTARGET investigators found no significant difference in any clinical efficacy outcome, but greater medication discontinuation in those treated with an ACEI or a combination of an ACEI and an ARB compared to those treated with an ARB alone. It is likely that combining studies reporting identical outcomes, but in different target populations, may yield important new information, particularly for rarer events such as cancer risk, angioedema, and mortality. Future research should consider this strategy and evaluate the extent to which results differ across target condition.
  4. The incidence, timing, and clinical consequences of angioedema in patients treated with ACEIs, ARBs, or direct renin inhibitors.
    Comment: Angioedema is a well-known adverse reaction to ACEIs and ARBs; however, because of its infrequent occurrence, we lacked sufficient evidence to directly compare the incidence, timing, and clinical consequences of this reaction among patients treated with ACEIs, ARBs, or direct renin inhibitors. Others have estimated that angioedema is experienced by 1 in every 1,000 patients treated with an ACEI,132,134 and 1 to 5 of every 10,000 of those treated with an ARB.135,136 Furthermore, others have reported a three- to fourfold increased risk of angioedema in African-American patients treated with an ACEI compared to Caucasian patients treated with an ACEI.131,132 Future research should utilize large databases with sufficient sample sizes to obtain more precise estimates of this rare but serious event. Assessment of study designs or analyses that could explore the impact of angioedema should be prioritized.
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Cover of Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), and Direct Renin Inhibitors for Treating Essential Hypertension: An Update
Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), and Direct Renin Inhibitors for Treating Essential Hypertension: An Update [Internet].
Comparative Effectiveness Reviews, No. 34.
Sanders GD, Coeytaux R, Dolor RJ, et al.

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