The renin-angiotensin system is a complex biologic system between the heart, brain, blood vessels, and kidneys that leads to the production of biologically active agents, including angiotensin I and II and aldosterone, which act together to impact a variety of bodily functions including blood vessel tone, sodium balance, and glomerular filtration pressure. The multiple and varied effects of these agents allows the renin-angiotensin system to play a wide role in the pathology of hypertension, cardiovascular health, and renal function.

Our ability to begin to intervene upon the complex cycle of hormone and other biochemical agent production within the renin-angiotensin system began with the advent of the first orally active ACE-I (angiotensin converting enzyme inhibitor), captopril, in 1981. ACE-Is interrupt the cycle within the renin-angiotensin system by blocking the conversion of angiotensin I to angiotensin II.1 Trials subsequent to the development of oral ACE-I agents demonstrated the broad impact of ACE-I inhibition. Inhibition of the renin-angiotensin system via ACE-I agents has now been found to be not only effective in the control of hypertension,2 but also reduces the risk of acute myocardial infarction among patients with heart failure,3 left ventricular remodeling after acute myocardial infarction,4 mortality among patients with severe heart failure and reduced left ventricular ejection fraction,5, 6 and progression of renal disease among diabetic and non-diabetic patients.7–10 While use of ACE-I inhibitors does diminish the amount of angiotensin II in circulation, it also leads to an increase in bradykinin, which is felt to be the etiology of some ACE-I-unique adverse effects such as cough.

AIIRAs (angiotensin II receptor blockers) were developed as an alternative to ACE-I, and block the interaction between angiotensin II and the angiotensin receptor. Losartan, the first commercially available AIIRA, was approved for clinical use in 1995. These agents offer benefits to ACE-Is with interruption of the renin-angiotensin system, but without an increase in bradykinin. The advent of AIIRAs resulted in a new option for those who could not tolerate ACE-I agents, and were found to yield similar results in terms of impact on hypertension, cardiovascular disease and heart failure, as well as renal disease progression.11–14 A newer type of agent, a DRI (direct renin inhibitor), has recently become available and may also be found to similarly impact these illnesses. Limited trial data are now available for these agents.

The strength of the evidence in support of renin-angiotensin system blockade has led to incorporation of ACE-Is and AIIRAs into important clinical guidelines. The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7) currently recommends an ACE-I or AIIRA as first line options for patients with stage 1 hypertension who have diabetes, chronic kidney disease, history of stroke or myocardial infarction, or high cardiovascular risk.15 The American Diabetes Association similarly recommends use of an ACE-I or AIIRA for diabetic patients with hypertension or diabetic nephropathy.16 That recommendation is echoed by the Kidney Disease Outcome Quality Initiative guidelines, which recommend ACE-Is or AIIRAs for patients with diabetic or non-diabetic proteinuric renal disease.17

Currently 11 ACE-Is, 7 AIIRAs, and 1 DRI are available in the United States and Canada (Table 1).

Table 1. Included drugs.

Table 1

Included drugs.

Purpose and Limitations of Systematic Reviews

Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. They focus on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with careful formulation of research questions. The goal is to select questions that are important to patients and clinicians then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix A and are defined as they apply to reports produced by the Drug Effectiveness Review Project.

Systematic reviews emphasize the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are preferred over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in each group, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant between groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat is the number of patients who would need be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards and, thereby, reducing the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well-executed randomized controlled trials are considered better evidence than results of cohort, case-control, and cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, well-conducted cohort designs are preferred for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted.

Systematic reviews pay particular attention to whether results of efficacy studies can be generalized to broader applications. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbiddisease, meaning disease other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that are impractical in typical practice settings. These studies often restrict options that are of value in actual practice, such as combination therapies and switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures, such as scores based on psychometric scales.

Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling a study as either an efficacy or an effectiveness study, although convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient.

Studies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how large the quantity, may have limited applicability to practice. Clinicians can judge the relevance of studies’ results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment.

In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The goal of this report is to compare the effectiveness and harms between aliskiren and placebo and between AIIRAs and ACEIs in the treatment of diagnosed coronary heart disease, hypertension, left ventricular dysfunction, heart failure, nondiabetic chronic kidney disease, or diabetic nephropathy. The Oregon Evidence-based Practi ce Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and, based on these, eligibility criteria for studies. A draft of these questions and inclusion and exclusion criteria were posted on the Drug Effectiveness Review Project website for public comment. Then, a group of clinicians specializing in nephrology and hypertension were consulted for clinical insight into the proposed key questions. The draft was reviewed and revised by representatives of the organizations participating in the Drug Effectiveness Review Project. Revision took into consideration input from the public, clinical advisors, and the organizations’ desire for the key questions to reflect populations, drugs, and outcome measures of interest to clinicians and patients. These organizations approved the following key questions to guide the review for this report:

  1. For adults with diagnosed coronary heart disease, hypertension, left ventricular dysfunction, heart failure, nondiabetic chronic kidney disease, or diabetic nephropathy, what is the effectiveness and efficacy and what are the harms of aliskiren compared with placebo?
    • 1a. When used as monotherapy?
    • 1b. When used in combination with angiotensin converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (AIIRA) drugs?
  2. For adults with diagnosed coronary heart disease, hypertension, left ventricular dysfunction, heart failure, nondiabetic chronic kidney disease, or diabetic nephropathy, what are the inter-class differences in effectiveness and efficacy between direct renin inhibitor (DRI), ACE-I and AIIRA drugs?
    • 2a. When used as monotherapy?
    • 2b. When used in combination with one another?
  3. For adults with diagnosed coronary heart disease, hypertension, left ventricular dysfunction, heart failure, nondiabetic chronic kidney disease, or diabetic nephropathy, what are the inter-class differences in harms between DRI, ACE-I and AIIRA drugs?
  4. Are there subgroups based on demographics (age, racial groups, gender), other medications, or co-morbidities for which there are inter-class differences between DRI, ACE-I and AIIRA drugs?