Drug Class Review on Angiotensin II Receptor Antagonists Final Report September 2004 The Agency for Healthcare Research and Quality has not yet seen or approved this report. Elaine Furmaga, PharmD Peter Glassman, MBBS, MSc Shannon Rhodes, MSPH Produced by Southern California Evidence-based Practice Center RAND 1700 Main Street, PO Box 2138 Santa Monica, CA 90407 Paul Shekelle, co-Director Sally Morton, co-Director Final Report Drug Effectiveness Review Project TABLE OF CONTENTS Introduction....................................................................................................................................4 Scope and Key Questions ..........................................................................................................5 Methods...........................................................................................................................................7 Literature Search........................................................................................................................7 Study Selection ..........................................................................................................................7 Data Abstraction ........................................................................................................................8 Quality Assessment....................................................................................................................8 Extraction of Adverse Event Data .............................................................................................9 Meta-Analysis of Adverse Event Data ......................................................................................9 Results ...........................................................................................................................................10 Overview..................................................................................................................................10 Question 1a. Outcomes: Essential Hypertension...................................................................11 Question 1b. Outcomes: High Cardiovascular Risk ..............................................................15 Question 1c. Outcomes: Recent Myocardial Infarction.........................................................17 Question 1d. Outcomes: Heart Failure...................................................................................19 Question 1e. Outcomes: Nephropathy ...................................................................................26 Question 2. Safety or Adverse Events .................................................................................30 Question 3. Safety and Efficacy: Patient Subgroups ...........................................................37 Summary and Discussion ............................................................................................................40 References.....................................................................................................................................45 In-text Tables Table 1. Guideline Recommendations on the Use of the Angiotensin II Receptor Antagonists ................................................................................................................4 Table 2. FDA Approved Indications for the Angiotensin II Receptor Antagonists .................5 Table 3. Comparison of Quality of Life in Patients with Hypertension ..................................12 Table 4. Comparison of VALIANT and OPTIMAAL Trial Results.......................................18 Table 5. Comparison of CHARM-Added and Val-HeFT Trial Results ..................................24 Table 6. Comparison of IDNT and RENAAL Trial Results ...................................................29 Table 7. Occurrence of selected adverse events in placebo-controlled trials of angiotensin II receptor antagonists ...........................................................................35 Table 8. Summary of the Evidence by Key Question..............................................................41 Table 9. Summary of the Evidence by Drug and Indication....................................................44 Figure Figure 1. Results of Literature Search .....................................................................................55 Angiotensin II Receptor Antagonists Page 2 of 408 Final Report Drug Effectiveness Review Project Evidence Tables Evidence Table 1. Active-controlled trials of AIIRAs in patients with hypertension.............56 Evidence Table 2. Placebo/active-controlled trials of AIIRAs in patients with hypertension..............................................................................................................86 Evidence Table 3. Active-controlled trials of AIIRAs in patients at high cardiovascular Risk ...........................................................................................................................96 Evidence Table 4. Active-controlled trials of AIIRAs in patients with recent myocardial infarction.................................................................................................................120 Evidence Table 5.Active-controlled trials of AIIRAs in patients with heart failure .............132 Evidence Table 6. Placebo-controlled trials of AIIRAs in patients with heart failure ..........160 Evidence Table 7. Active-controlled trials of AIIRAs in patients with nephropathy............202 Evidence Table 8.Placebo-controlled trials of AIIRAs in patients with nephropathy...........220 Evidence Table 9. Adverse events in randomized controlled trials of AIIRAs.....................230 Evidence Table 10. Studies of adverse events of AIIRAs......................................................272 Quality Tables Quality Table 1. Active-controlled trials of AIIRAs in patients with hypertension..............312 Quality Table 2. Placebo/active-controlled trials of AIIRAs in patients with hypertension...........................................................................................................317 Quality Table 3. Active-controlled trials of AIIRAs in patients at high cardiovascular risk..........................................................................................................................322 Quality Table 4. Active-controlled trials of AIIRAs in patients with recent myocardial infarction.................................................................................................................327 Quality Table 5. Active-controlled trials of AIIRAs in patients with heart failure ...............332 Quality Table 6. Placebo-controlled trials of AIIRAs in patients with heart failure .............347 Quality Table 7. Active-controlled trials of AIIRAs in patients with nephropathy...............357 Quality Table 8. Placebo-controlled trials of AIIRAs in patients with nephropathy.............369 Quality Table 9. Quality assessment of randomized controlled trials of adverse events with AIIRAs ...................................................................................................................375 Quality Table 10. Quality assessment of adverse events trials with AIIRAs ........................385 Appendices Appendix A. Search Strategies ..............................................................................................389 Appendix B. Criteria for Rating Observational Studies of Adverse Events..........................391 Appendix C. Included Articles ..............................................................................................392 Appendix D. Excluded Articles .............................................................................................400 Angiotensin II Receptor Antagonists Page 3 of 408 Final Report Drug Effectiveness Review Project INTRODUCTION The angiotensin II receptor antagonists (AIIRAs, also referred to as ARBs or angiotensin receptor blockers) selectively inhibit angiotensin II from activating the angiotensin II type 1 receptor (AT1). This action blocks vasoconstriction, sodium and water retention, activation of the sympathetic nervous system, constriction of the afferent and efferent arteriole in the kidney, and stimulation of vascular and myocardial fibrosis.1 The mechanism of action of the angiotensin II receptor antagonists differs from that of the angiotensin-converting enzyme inhibitors (ACEI) in that the ACEIs block the conversion of angiotensin I to angiotensin II. Since angiotensin II can be produced by other enzymes, its effects are not entirely blocked by ACEIs. In addition, the ACEIs interfere with the breakdown of bradykinin and substance P, which is thought to be the cause of some of their side effects, including cough and angioedema. Like the ACEIs, the angiotensin II receptor antagonists are useful in the management of patients with hypertension (HTN), patients at high cardiovascular (CV) risk, patients with CV disease such as heart failure (HF) or myocardial infarction (MI) complicated by heart failure of left ventricular dysfunction (LVD), and patients with diabetes mellitus (DM) and renal disease. Whether the angiotensin II receptor antagonists are equivalent to the ACEIs in their renal and cardioprotective effects is being evaluated in clinical trials. A summary of recommendations from clinical practice guidelines and/or Associations or Committees on therapy with the angiotensin II receptor antagonists are included in Table 1. Table 1. Guideline Recommendations on the Use of Angiotensin