Background

Almost 75 million American adults—approximately one-third—have hypertension. The prevalence of hypertension increases with advancing age such that more than half of people 55 to 74 years old and approximately three-fourths of those age 75 years and older are affected.¹ In addition to being the primary attributable risk factor for death throughout the world,² hypertension results in substantial morbidity because of its impact on numerous target organs, including the brain, eyes, heart, arteries, and kidneys.

Despite the high morbidity and mortality attributable to hypertension and recent improvements in hypertension treatment, control of the condition remains suboptimal. Approximately one-quarter of adults remain unaware of their hypertension, one-third of individuals with hypertension are not on treatment, and one-half of hypertensive patients continue to have blood pressure above even modest treatment goals (< 140/90 mmHg).³ Several nonpharmacological interventions—including diet, exercise, and control of body weight—are effective in lowering blood pressure; however, such therapies are often insufficient or not sustained, resulting in reliance on pharmacotherapy. Various classes of antihypertensive drug treatments are available, but determining their comparative effectiveness is complicated. Therapeutic choices may be influenced by patient characteristics—including comorbidities and race—that also affect the risk of certain clinical end points. Multidrug therapy is often required to achieve satisfactory control, leading to greater variables to consider in treatment choices.⁴ Finally, adverse events that are characteristic of the individual agents or drug classes further complicate therapeutic decisionmaking.

Among the many choices in antihypertensive therapy, some of the most common are those aimed at affecting the renin-angiotensin-aldosterone (renin) system. The renin system is an important mediator of blood volume, arterial pressure, and cardiac and vascular function. Components of this system can be identified in many tissues, but the primary site of renin release is the kidney. The renin system can be triggered by sympathetic stimulation, renal artery hypotension, and decreased sodium delivery to the distal tubule. Through proteolytic cleavage, renin acts on the oligopeptide substrate angiotensinogen to produce the decapeptide angiotensin I. In turn, two terminal peptide residues of angiotensin I are removed by the angiotensinconverting enzyme (ACE) to form the octapeptide angiotensin II. Angiotensin II acts directly on the resistance vessels to: increase systemic vascular resistance and arterial pressure; stimulate the adrenal cortex to release aldosterone, which leads to increased sodium and water reabsorption and potassium excretion; promote secretion of antidiuretic hormone, which leads to fluid retention; stimulate thirst; promote adrenergic function; and increase cardiac and vascular hypertrophy.

Therapies aimed at modifying the renin system have been used extensively for treatment of hypertension, heart failure, myocardial infarction (MI), diabetes, and renal disease.^5,6 Currently, three classes of drugs that interact with this system are used to inhibit the effects of angiotensin II: the angiotensin-converting enzyme inhibitors (ACEIs); the angiotensin II receptor antagonists (ARBs); and the direct renin inhibitors. ACEIs block the conversion of angiotensin I into angiotensin II; ARBs selectively inhibit angiotensin II from activating the angiotensin specific receptor (AT₁); and direct renin inhibitors block the conversion of angiotensinogen into angiotensin I.

Although ACEIs, ARBs, and direct renin inhibitors all target the renin system and are often treated by clinicians as being equivalent, this may not be appropriate. While all three drug classes reduce the downstream effects of angiotensin II, there are differences that may distinguish them. ACEIs, for example, do not entirely block production of angiotensin II because of the presence of unaffected converting enzymes. Treatment with an ACEI, but not an ARB, results in increased levels of bradykinin, and this mechanism may mediate differences in clinical efficacy or side effects such as cough or angioedema. Unlike ACEIs and direct renin inhibitors, ARBs selectively block the effects of angiotensin II at the AT₁ receptor. Both ACEIs and ARBs result in compensatory increases in plasma renin activity, an effect not shared by direct renin inhibitors.⁷ ACEIs have well-known side effects not shared by ARBs, including cough (estimated incidence 5 to 20 percent) and angioedema (estimated incidence 0.1 to 0.2 percent, with a lesser reported risk with ARBs).⁸ Although ACEIs, ARBs and direct renin inhibitors are highly effective in lowering blood pressure among patients with essential hypertension,^5,6 the comparative effectiveness of these medication classes is not known. ACEIs and ARBs are the second and fifth most commonly prescribed medications for hypertension, respectively, and the use of direct renin inhibitors has been rising since their introduction.⁹ Although ACEIs and ARBs are occasionally used in combination, such combinations provide little blood pressure lowering over each agent used alone,¹⁰ and are associated with increased adverse events.¹¹ As a result, most providers choose to use either an ACEI or an ARB for hypertension. It is therefore important to understand the comparative effectiveness of these agents for providers making this choice.

In this comparative effectiveness review, which updates the 2007 report Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Antagonists (ARBs) for Treating Essential Hypertension,¹² we examine the scientific literature on ACEIs, ARBs, and direct renin inhibitors for individuals with hypertension. The outcomes analyzed in this comparison are the relative benefits (i.e., blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes), as well as safety (i.e., adverse events, tolerability, persistence with drug therapy, and treatment adherence). Moreover, we examine the clinical determinants of these outcomes, such as age, race, ethnicity, sex, comorbidities, and concurrent use of other medications. The focus is on long-term outcomes and impact.

The need for this updated report was determined by an analysis conducted by the Southern California Evidence-based Practice Center.¹³ In that analysis, investigators assessed the conclusions from the original comparative effectiveness review, performed a limited literature search of potentially new evidence, and solicited expert opinions concerning the state of the evidence and validity of the original report.

Scope and Key Questions

This review summarizes the evidence on the comparative long-term benefits and harms of ACEIs, ARBs, and direct renin inhibitors for treating essential hypertension in adults. Key Questions addressed are:

• Key Question 1. For adult patients^a with essential hypertension, how do ACEIs (angiotensin-converting enzyme inhibitors), ARBs (angiotensin II receptor antagonists), and direct renin inhibitors^b differ in blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes^c?
• Key Question 2. For adult patients with essential hypertension, how do ACEIs, ARBs, and direct renin inhibitors differ in safety,^d adverse events,^e tolerability, persistence with drug therapy, and treatment adherence?
• Key Question 3. Are there subgroups of patients—based on demographic and other characteristics (i.e., age, race, ethnicity, sex, comorbidities, concurrent use of other medications)—for whom ACEIs, ARBs, or direct renin inhibitors are more effective, are associated with fewer adverse events, or are better tolerated?

Table 1

Characteristics and labeled indications of ACEIs, ARBs, and direct renin inhibitors evaluated in this report.

Footnotes

a

“Adult patients” are defined as adults, age 18 years or older.

b

Table 1 lists the specific ACEIs, ARBs, and direct renin inhibitors evaluated in this review and describes their characteristics and current indications.

c

Outcomes considered include:

Primary outcomes:

1. Blood pressure control (we will prefer seated trough blood pressure, where reported).
2. Mortality (all-cause, cardiovascular disease-specific, and cerebrovascular disease-specific).
3. Morbidity (especially major cardiovascular events [myocardial infarction (MI), stroke] and measures of quality of life).
4. Safety (focusing on serious adverse event rates, overall adverse event rates, and withdrawals due to adverse events, withdrawal rates, and switch rates).
5. Specific adverse events (including, but not limited to, weight gain, impaired renal function, angioedema, cough, and hyperkalemia).
6. Persistence/adherence.
7. Rate of use of a single antihypertensive medication for blood pressure control.

Secondary outcomes:

1. Lipid levels (high-density lipoprotein, low-density lipoprotein, total cholesterol, and triglycerides).
2. Rates of progression to type 2 diabetes.
3. Markers of carbohydrate metabolism/diabetes control (glycated hemoglobin [HbA1c], dosage of insulin or other diabetes medication, fasting plasma glucose, or aggregated measures of serial glucose measurements).
4. Measures of left ventricular mass/function (left ventricular mass index and ejection fraction).
5. Measures of kidney disease (creatinine/glomerular filtration rate [GFR], proteinuria).

d

Safety outcomes considered include: Overall adverse events, withdrawals due to adverse events, serious adverse events reported, withdrawal rates, and switch rates. (For practical reasons, we separate safety/adverse events and tolerability/persistence [including switch rates], as the latter may or may not be due to identifiable adverse events.)

e

Specific adverse events: These included, but were no limited to, weight gain, impaired renal function, angioedema, cough, and hyperkalemia.