1. ACEIs, ARBs, or DRI for Adults With Hypertension Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

2.  Approximately 75 million Americans have hypertension.  The prevalence of hypertension increases with advancing age.  More than half of people 55 to 74 years old and approximately three-fourths of those ≥75 years are affected.  Hypertension is the primary attributable risk factor for death and results in substantial morbidity.  Hypertension impacts numerous target organs, including the brain, eyes, heart, arteries, and kidneys. Background: Prevalence

3.  Despite the high rates of morbidity and mortality attributable to hypertension, control of the condition remains suboptimal.  Effective lifestyle interventions may include diet, exercise, and control of body weight.  Many people also require antihypertensive medication to lower blood pressure. Background: Treatment

4. Background: Pharmacological Blockade of the Renin-Angiotensin System  Among the many choices in antihypertensive therapy, some of the most common are those aimed at affecting the renin- angiotensin-aldosterone (renin) system. These include:  Angiotensin Converting Enzyme Inhibitors (ACEIs)  Angiotensin II Type I Receptor Blockers (ARBs)  Direct Renin Inhibitor (DRI)

5.  Although ACEIs and ARBs both target the renin system and reduce the downstream effects of angiotensin II, it is not clear that these medications are in fact clinically equivalent.  ACEIs only block partial production of angiotensin II.  ACEIs have well-known side effects not shared to the same extent by ARBs, including cough and angioedema.  The newer DRI aliskiren may have a side-effect profile and efficacy that differ significantly from ACEIs or ARBs.  Given the public health importance and widespread use of these agents, it is important to understand their comparative effects on clinical outcomes. Background: Drugs Targeting The Renin System May Not Be Clinically Equivalent

6.  In 2007, AHRQ published its first systematic review on the comparative effectiveness of ACEIs versus ARBs for adults with hypertension.  In 2011, this review was updated to include comparisons with the DRI aliskiren.  ACEIs and ARBs are the second and fifth most commonly prescribed medications for hypertension, and use of DRI is increasing.  Comparative effectiveness of the DRI versus ACEIs or ARBs has not been assessed. Rationale for Update

7.  Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into Clinician and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The research reviews and the full report, with references for included and excluded studies, are available at: www.effectivehealthcare.ahrq.gov. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development

8.  The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the CER HighFurther research is very unlikely to change the confidence in the estimate of effect. ModerateFurther research may change the confidence in the estimate of effect and may change the estimate. LowFurther research is likely to change the confidence in the estimate of effect and is likely to change the estimate. InsufficientEvidence either is unavailable or does not permit estimation of an effect.

9. Number of Studies Evaluating Various Treatment Options ARBsDRI Unspecified “ARBs” Candesartan cilexetil EprosartanIrbesartanLosartanOlmesartan medoxomil TelmisartanValsartanAliskiren ACEIs Unspecified “ACEIs” 2010220000 Benazepril 000000010 Captopril 000020000 Enalapril 0424130520 Fosinopril 000210000 Lisinopril 060000350 Moexipril 000000000 Perindopril 010020300 Quinapril 000230000 Ramipril 000021532 Trandolapril 000010000 DRIAliskiren 00001000-

10.  Similar long-term blood pressure-lowering effects were seen with ACEIs and ARBs. (high strength of evidence)  The DRI aliskiren may be slightly more effective at reducing blood pressure than an ACEI (ramipril); however, no differences were detected between aliskiren and an ARB (losartan). (low strength of evidence) Evidence of Benefits: Blood Pressure-Lowering Effects

11.  There were no significant differences between ACEIs and ARBs for these outcomes:  Mortality and major cardiovascular events (low strength of evidence)  Rate of monotherapy success (high strength of evidence)  Quality of life measures (low strength of evidence)  Progression of renal disease (moderate strength of evidence)  Effects on LVMI or LVEF (low strength of evidence)  ACEI and ARBs are similar in their lack of effect on serum lipid levels, blood glucose levels, and HbA1c. (moderate strength of evidence)  There was insufficient evidence for all other outcomes beyond blood pressure reduction on the comparative effectiveness of the DRI aliskiren. Evidence of Benefits: Clinical Outcomes

12.  Cough is more prevalent in patients on ACEIs than ARBs (About 9% of patients treated with an ACEI and about 2% of patients treated with an ARB report a cough). —(high strength of evidence)  ACEIs were associated with lower rates of persistence and higher rates of withdrawals due to adverse events when compared with ARBs. (moderate strength of evidence)  Lower persistence with ACEIs versus ARBs may be explained largely by the differential rates of cough.  Excluding cough, there were no significant between-class differences in any other specific adverse events. Evidence on Adverse Effects

13.  Angioedema was uncommon and most frequently associated with ACEIs.  In one study, the DRI was associated with angioedema in one patient, but overall the evidence was insufficient. Evidence on Adverse Effects: Angioedema

14.  Long-term comparisons of a DRI with ACEIs and ARBs.  The impact of cough on quality of life, care patterns (e.g., use of therapeutic agents for cough symptoms or conditions associated with cough), and health outcomes, particularly for individuals who continue to use ACEIs.  Subgroups of special importance such as individuals with hypertension and diabetes mellitus, congestive heart failure, chronic kidney disease, and dyslipidemia.  Broader representation of groups such as the elderly and ethnic and racial minorities.  Clinical trials with long-term followup that report on the incidence of new cancer diagnoses and cancer deaths in patients on ACEIs, ARBs, or a DRI. Gaps in Knowledge

15.  Medication costs may contribute to decreased adherence among patients.  Average wholesale prices for these antihypertensive agents range from $30 to $160 per month, depending on dosage.  On average, ACEIs are less expensive for patients than ARBs and the DRI aliskiren.  The most inexpensive ACEIs for patients are the generic forms of benazepril, enalapril, lisinopril, and quinapril.  The majority of ARBs are not available in generic form. The average cost of most brand-name ARBs is between $80 and $195 per month, depending on dosage.  The DRI aliskiren is also not available in a generic form. The average wholesale cost of aliskiren is $100 or $120 per month, depending on dosage. Patient Cost Information

16.  The importance of taking blood pressure medication as prescribed.  The tradeoffs between the benefits and adverse effects when taking an ACEI, ARB, or DRI.  How to identify and when to report serious side effects.  Barriers that may affect adherence to their specific treatment regimen.  All other medications they may be taking and their possible interactions. What To Discuss With Your Patients