angiotensin-converting enzyme inhibitors (aceis), angiotensin ii receptor antagonists (arbs), and...

Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Antagonists

(ARBs), and Direct Renin Inhibitors for Treating Essential Hypertension: An Update

First Last, Credentials

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First, Last, CredentialsSpeaker


Learning Objectives– Compare the effectiveness of ACE inhibitors, ARBs, and

direct renin inhibitors for controlling blood pressure and reducing risks of cardiovascular mortality and morbidity

– Assess key differences in side-effect profiles, tolerability, and persistence outcomes associated with ACE inhibitors, ARBs, and direct renin inhibitors

– Apply findings from the systematic review to guide decisions about appropriate patient-centered therapies for managing hypertension

Challenge of Managing Hypertension

• Affects ~ 65 million American adults– 3rd decade ~30%– 5th decade ~50%– 7th decade ~70%– 8th decade ~ 80%

• Leading risk factor for death worldwide

• Adverse effects on many organs• Decreasing systolic BP by 10mm

Hg reduces risk: • Of stroke by ~ 35%• Of ischemic heart disease events by

~ 25%Egan BM, et al. JAMA. 2010;303:2043-2050. Law, MR et al. BMJ. 2003;326:1427-1431.

• Among adults with hypertension 25% unaware of their condition 33% aware but not on treatment 50% on treatment but above

even modest BP goals• Hypertension is especially

prevalent among African Americans and Hispanics

• Responses to individual medications can vary widely across patients

• Adverse effects may complicate treatment decisions

Key Questions• Key Question 1. For adult patients with essential hypertension, how do

ACEIs (angiotensin-converting enzyme inhibitors), ARBs (angiotensin II receptor antagonists), and direct renin inhibitors differ in blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes?

• Key Question 2. For adult patients with essential hypertension, how do ACEIs, ARBs, and direct renin inhibitors differ in safety, adverse events, 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?

Search Strategy for Systematic Review

2090 citations identified by literature search

1007 passed abstract screening

328 direct comparator trials screened at full-text stage

110 direct comparator articles abstracted into evidence tables

and included in review

1083 abstracts excluded

679 articles reviewed separately:• 276 review articles• 403 indirect comparator studies

218 articles excluded:• 119 follow-up <12 weeks• 10 not essential hypertension• 26 no direct comparison of drugs• 11 no separate results for subgroup with

hypertension• 52 other

Medications included in this reportAngiotensin Converting Enzyme Inhibitor (Trade Name)

Angiotensin Receptor Blocker (Trade Name)

Direct Renin Inhibitor (Trade Name)

Benazepril (Lotensin) Candesartan cilexetil (Atacand) Aliskiren (Tekturna)

Captopril (Capoten) Eprosartan (Teveten)

Enalapril (Vasotec) Irbesartan (Avapro)

Fosinopril (Monopril) Losartan (Cozaar)

Lisinopril (Prinivil; Zestril) Olmesartan medoxomil (Benicar)

Moexipril (Univasc) Telmisartan (Micardis)

Perindopril (Aceon) Valsartan (Diovan)

Quinapril (Accupril)

Ramipril (Altace)

Trandolapril (Mavik)

Sanders, GD et al. Rockville, MD: Agency for Healthcare Research and Quality. June 2011. http://www.effectivehealthcare.ahrq.gov/ehc/products/164/695/CER-34-ACEIs-ARBs_Executive-Summary_20110613.pdf

Grading the Strength of Evidence• Grading scheme similar to the “Grading of Recommendations

Assessment, Development, and Evaluation” framework used in 2007 report

• Considerations: number of studies, the size of the studies, strength of study design, and the quality of individual studies

• Strength of evidence classified into 4 categories:

e

High High confidence that the evidence reflects the true effect. Further research is very unlikely to change our confidence in the estimate of effect.

Moderate Moderate confidence that the evidence reflects the true effect. Further research may change our confidence in the estimate of effect and may change the estimate.

Low Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.

Insufficient Evidence is either unavailable or does not permit estimation of an effect.

Outcomes of Interest• Primary outcomes

– Blood pressure control– Mortality

– all-cause, cardiovascular disease-specific, cerebrovascular disease-specific

– Morbidity – MI, stroke, and measures of quality

of life

– Safety – (serious AE rates, overall AE rates,

withdrawal rates, switch rates)

– Specific adverse effects – weight gain, impaired renal

function, angioedema, cough, hyperkalemia

– Persistence/adherence

– Rate of use of a single medication for BP control

• Secondary outcomes– Lipid levels (HDL, LDL, TC, TG)– Rates of progression to type 2

diabetes– Markers of carbohydrate

metabolism/diabetes control – HbA1c, dosage of diabetes meds,

fasting plasma glucose, aggregated measures of serial glucose measurements

– Measures of left ventricular mass/function (LVMI and LVEF)

– Measures of kidney disease – GFR, proteinuria

KEY QUESTION 1:

Blood Pressure ControlMortality and Major Cardiovascular EventsQuality of Life Rate of use of a single antihypertensive medicationRisk factor reduction and other intermediate outcomes

For adult patients with essential hypertension, how do ACEIs (angiotensin-converting enzyme inhibitors), ARBs (angiotensin II receptor antagonists), and direct renin inhibitors differ in blood pressure control, cardiovascular risk reduction, cardiovascular events, quality of life, and other outcomes?

Overview of BP ReductionComparison Outcome Strength of

Evidence

ACEI vs. ARB70 RCTsN=26,170

ACEIs and ARBs appear to have similar long-term effects on BP• No difference: 57 studies• ACEI favored: 2 studies• ARBs favored 11 studies

High

DRI vs. ACEI or ARB3 Studies

DRIs appear to have a greater reduction in blood pressure compared to the ACEI ramipril (2 studies) and no significant difference compared to the ARB losartan (1 study).

Low

ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin II receptor blockerDRI = direct renin inhibitor


Overview of Mortality and Major Cardiovascular Events

Comparison Outcome Strength of Evidence

ACEI vs. ARB21 StudiesN=38,589

No discernable differences for these critical outcomes

Low

DRI vs. ACEI or ARB3 StudiesN=2,049

No discernable differences for these critical outcomes

Insufficient


• Low number of reported deaths (39) and strokes (13)• Study limitations

• Most excluded patients with CV disease and other comorbidities• Short duration of follow-up


Overview of Quality of LifeComparison Outcome Strength of

Evidence

ACEI vs. ARB4 Studies

No differences were found in measures of general quality of life • 2 studies did not provide quantitative

data

Low

DRI vs. ACEI or ARBNo Studies

No study evaluated the comparative effectiveness of direct renin inhibitors for quality-of-life outcomes.

Insufficient



Overview of Rate of Use of a Single Antihypertensive Medication

Comparison Outcome Strength of Evidence

ACEI vs. ARB26 Studies• 23 RCTs, • 3 Observational

No statistically evident difference in the rate of treatment success based on use of a single antihypertensive for ARBs compared to ACEIs

High

DRI vs. ACEI or ARBNo Studies

No relevant studies evaluating direct renin inhibitors

Insufficient



Overview of Risk Factor Reduction and Other Intermediate Outcomes

Comparison Outcome: Lipid levels, markers of carbohydrate metabolism/ diabetes control, progression of renal disease:

Strength of Evidence

ACEI vs. ARB • No consistent differential effects on several clinical outcomes, including lipid levels and markers of carbohydrate metabolism/diabetes control

• Small difference (but likely not clinically meaningful in change in renal function between ACEIs and ARBs (favoring ACEIs)

Moderate

DRI vs. ACEI or ARB There were no studies that evaluated these outcomes in direct renin inhibitors.

Insufficient



Overview of Risk Factor Reduction and Other Intermediate Outcomes• Comparison Outcome: (this summary applies to both

comparison groups)Progression to type 2 diabetes and LV mass/ function:

Strength of Evidence

• ACEI vs. ARB • No evidence for an impact of ACEIs, ARBs, or direct renin inhibitors on glucose or A1c and no included studies evaluated rates of progression to type 2 diabetes mellitus.

• 13 studies of LV mass/ function, but most were poor-quality studies with small sample sizes, and only one study included evaluation of a direct renin inhibitor

Low

• DRI vs. ACEI or ARB

Insufficient



KEY QUESTION 2

Withdrawals due to adverse eventsAngioedemaPersistence with drug therapy/treatment adherence

For adult patients with essential hypertension, how do ACEIs, ARBs, and direct renin inhibitors differ in safety, adverse events, tolerability, persistence with drug therapy, and treatment adherence?

Overview of CoughComparison Outcome: Strength of

Evidence


ACEIs consistently associated with greater risk of cough than ARBs (odds ratio 0.211; 95% CI 0.159 to 0.281) • For RCTs, this translates to a

difference in rates of cough of 7.8 percent

• For cohort studies with lower rates of cough, this translates to a difference of 1.2 percent

High

DRI vs. ACEI or ARB2 StudiesN=1,743(aliskiren vs ramipril)

These 2 studies gave an estimated odds ratio of 0.333 (95% CI 0.2241 to 0.4933).

Insufficient



Overview of Withdrawals Due to Adverse Events

Comparison Outcome: Strength of Evidence


Withdrawal rates were significantly lower for ARBs vs. ACEIs•Total withdrawal rates ranged 1% – 20%•Mean withdrawal rates: 3% for ARBs and 5% ACEI

High

DRI vs. ACEI or ARB2 StudiesN=1,743(aliskiren vs ramipril)

DRI trials did not find a statistically significant difference (odds ratio 0.886; 95% CI 0.458 to 1.714) when compared with the withdrawal rate associated with ACEIs

Low



Overview of AngioedemaComparison Outcome: (this summary applies to both

comparison groups)Strength of Evidence

ACEI vs. ARB • The event rates were very low or zero for all studies limiting ability to accurately characterize the frequency of angioedema

• Only 6 cases in 4 studies it was observed only in patients treated with an ACEI (4 for lisinopril and 1 for enalapril in three studies) or a direct renin inhibitor (1patient in 1 study)

Low

DRI vs. ACEI or ARB Insufficient


Conclusion: Due to insufficient evidence, no clinically relevant conclusions could be reached


Overview of Persistence with Drug Therapy / Treatment Adherence

Comparison Outcome: Strength of Evidence

ACEI vs. ARB • Adherence rates: No differences between patients treated with ARBs vs ACEIs

• Persistence rates: Slightly greater persistence among patients treated with ARBs vs ACEIs

Moderate

DRI vs. ACEI or ARB • Adherence rates: No differences between patients treated with ARBs vs ACEIs or DRI

• Persistence was not evaluated in any of the studies including direct renin inhibitors.

Insufficient


Adherence = Number of pills taken Persistence = Number of patients remaining on therapy

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?

Overview of Subgroup Analysis

• Few studies were designed to assess treatment-related differences within patient subgroups

• For BP reduction, most studies revealed no significant differences in efficacy between ACEIs, ARBs, and aliskiren within subgroups studied– Women, African Americans, older adults

• For all other outcomes, the evidence was insufficient to reach conclusions


CLINICAL BOTTOM LINE

Clinical Bottom LineACEIs vs ARBs DRI vs ACEI DRI vs ARB

Key Question 1: BenefitsBlood pressure control ND ●●● Favors DRI ● ND ●

Mortality and CV events ND ● IE IE

Quality of life ND ● NE NESuccess on monotherapy ND ●●● NE NE

Lipids, markers of diabetes and renal disease

ND ●● NE NE

Key Question 2: RisksCough Favors ARBs ●●● IE NE

Withdrawal due to adverse events Favors ARBs ●●● ND ● NE

Angioedema IE IE IEAdherence ND ●● IE IE

Persistence Favors ARBs ●● IE NE

ND = No difference; NE = No evidence; IE = Insufficient evidence; ● = Low strength of evidence; ●● = Moderate strength of evidence; ●●● = High strength of evidence

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REMAINING ISSUES

Gaps in Knowledge

Limitations of AHRQ Review• Lack of quality RCTs / observational

studies• Limited number of long-term

clinical outcomes studies • Poor controls for dose escalation

and added therapies• Inconsistent adverse events

reporting• Few studies on the effects of DRIs

vs. ACEIs or ARBs• Insufficient evidence for patient

subgroups

• Broader representation of patient subgroups

• Subgroup analyses of patients with essential hypertension and various comorbid conditions

• Studies focusing on treatment consistent with typical clinical practice

• Assessment of long-term clinical outcomes

• Long-term comparisons of DRIs with ACEIs and ARBs

• Evaluation of therapies within a class

Future Research

Remaining Issues

Thank you for the opportunity to share this information with you• For CE/CME:– ce.effectivehealthcare.ahrq.gov/credit– Enter code: CER28

• For electronic copies of the clinician guide, the consumer guide, and the full systematic review– www.ahrq.gov

• For free print copies– AHRQ Publications Clearinghouse (800) 358-9295

We encourage you to visit AHRQ’s continuing education website regularly to participate in future programs.

angiotensin-converting enzyme inhibitors (aceis), angiotensin ii receptor antagonists (arbs), and...

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