Introduction

Our review of the literature on the comparative long-term benefits and harms of angiotensin-converting enzyme inhibitors (ACEIs) versus angiotensin II receptor antagonists (ARBs) for treating hypertension focused, in the first instance, on direct head-to-head comparisons of drugs in the two classes. Because we were uncertain that these direct comparisons would adequately address all aspects of the key questions, we also sought to identify and screen potentially relevant indirect comparison studies – that is, studies in which ACEIs and ARBs were compared, in distinct trials, with a common comparator. This Appendix describes the methods we used to identify and review indirect comparison studies.

Search and Abstract Screening

We began by searching MEDLINE^® for studies of ARBs versus other (non-ACEI) comparators, including placebo (see MEDLINE^® Search 1 in Appendix A). We screened these abstracts along with the head-to-head trials (see the abstract screening criteria in Appendix C). Note that, for indirect comparisons, we considered only randomized controlled trials (RCTs). We coded each included abstract for treatment duration/length of followup (“12 weeks”, “1 year”, etc.).

Because a primary objective for evaluating non-head-to-head studies was to expand the pool of evidence regarding long-term results, we restricted the pool of abstracts for further evaluation to those with a treatment duration/length of followup of ≥24 weeks. Further, since the credibility of any meta-analysis – particularly for non-head-to-head trials – depends on consistency among studies, we considered only comparators for which there were ≥3 trials. The comparators thus identified were atenolol, amlodipine, and placebo.

Next, we searched MEDLINE^® for studies of ACEIs versus atenolol or amlodipine (see MEDLINE^® Search 2 in Appendix A). To identify potentially relevant ACEI-versus-placebo trials, we began by searching the references of the June 2005 Drug Class Review on Angiotensin Converting Enzyme Inhibitors^* and supplemented this with a search of MEDLINE^® for articles published after that review (see MEDLINE^® Search 3 in Appendix A). Finally, the abstracts for all ACEI-versus-other studies were screened for inclusion and evaluated further to identify trials with the right treatment duration/length of followup (≥24 weeks) and the right comparators (atenolol, amlodipine, or placebo).

The result of this process was that we identified 76 RCT publications comparing ARBs with atenolol, amlodipine, or placebo over a period of ≥24 weeks, and 136 RCT publications comparing ACEIs with the same group of comparators over the same period of time. We were unable to obtain copies of four articles (two each for ACEIs and ARBs), so the final counts were 74 potentially relevant ARB articles and 134 potentially relevant ACEI articles.

Identifying Publications Reporting Outcomes of Interest

Once data from the direct comparator trials had been abstracted, we identified three categories of outcomes that we thought were under-reported in these trials:

• Mortality and major events (myocardial infarction [MI], stroke);
• Measures of carbohydrate metabolism/diabetes control (progression to type 2 diabetes, glycated hemoglobin [HgbA1c], insulin or other diabetes medication dosage, fasting plasma glucose, or aggregated measures of serial glucose measurements);
• Measures of kidney disease (creatinine/glomerular filtration rate [GFR] and proteinuria).

We then screened the indirect comparison literature identified through the process described above in full-text form to identify publications that reported on one or more of these outcomes. Thirty-two (32) ARB-versus-other publications and 42 ACEI-versus-other publications reported one or more of the outcomes of interest and were evaluated further. A list of these 74 publications is provided at the end of this Appendix.

Analysis of Comparability of Trials

In consideration of the special challenges of using indirect (non-head-to-head) comparison studies to infer relative efficacy regarding any particular health outcome, we established minimal criteria before considering any indirect comparison. Our goal was to achieve a reasonable degree of clinical homogeneity without being excessively restrictive at this stage.

We defined three criteria for considering performing an indirect comparison. The first criterion was that the studies must have a common comparator (amlodipine, atenolol, or placebo). The rationale is that comparators cannot be considered equivalent with regard to any particular health outcome. The second criterion was that study populations must be generally comparable, at least with regard to key characteristics relevant to the outcome being assessed. For studies examining event rates (mortality, stroke, or MI), the key characteristic was the mean age of the population. For studies of laboratory measures (HgbA1c, glucose, creatinine, GFR, or proteinuria), the key characteristic was the mean of the corresponding laboratory measure at baseline. The value for the key characteristic could be different by as much as 10 percent and still be considered to be comparable (e.g., for mortality rates in which the study with the highest mean age for subjects was 70 years, comparable studies could have mean subject ages as low as 63 years). The third criterion was that among studies satisfying the preceding criteria, there must be more than one study of an ACEI versus the comparator and more than one study of an ARB versus the comparator. That is, indirect comparisons for a particular outcome would be considered only if there were at least four comparable studies to evaluate, two for an ACEI and two for an ARB. Notably, we did not restrict studies to the same ACEI or ARB, or any other protocol characteristics.

Despite these relatively liberal criteria for considering indirect comparisons between ACEIs and ARBs, we did not identify any appropriate candidate studies related to an outcome of special interest, and thus we did not attempt to use indirect evidence to infer relative impact of ACEIs versus ARBs.

List of Indirect Comparator Articles Reaching the Final Stage of Evaluation

The following is a list of the 74 indirect comparator publications that met our basic screening criteria (RCT, followup ≥24 weeks, comparator with ≥3 trials on ACEI and ARB sides) and reported one or more of the outcomes of interest specified above (mortality, MI, stroke, diabetes outcomes, kidney disease outcomes).

Aberg H, Morlin C, Lithell H. Different long-term metabolic effects of enalapril and atenolol in patients with mild hypertension. EGTA Group. J Hum Hypertens 1995;9(2):149–53.

Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001;285(21):2719–28.

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)[erratum appears in JAMA 2003 Jan 8;289(2):178]. JAMA 2002;288(23):2981–97.

Anonymous. The treatment of mild hypertension study. A randomized, placebo-controlled trial of a nutritional-hygienic regimen along with various drug monotherapies. The Treatment of Mild Hypertension Research Group. Arch Intern Med 1991;151(7):1413–23.

Anonymous. Hypertension in Diabetes Study. III. Prospective study of therapy of hypertension in type 2 diabetic patients: efficacy of ACE inhibition and beta-blockade. Diabet Med 1994;11(8):773–82.

Anonymous. Hypertension in Diabetes Study IV. Therapeutic requirements to maintain tight blood pressure control.[erratum appears in Diabetologia 1997 Mar;40(3):366]. Diabetologia 1996;39(12):1554–61.

Anonymous. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998;317(7160):713–20.

Anonymous. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group[erratum appears in BMJ 1999 Jan 2;318(7175):29]. BMJ 1998;317(7160):703–13.

Arima H, Hart RG, Colman S, et al. Perindopril-based blood pressure-lowering reduces major vascular events in patients with atrial fibrillation and prior stroke or transient ischemic attack. Stroke 2005;36(10):2164–9.

Bakris GL, Weir MR, Shanifar S, et al. Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med 2003;163(13):1555–65.

Berl T, Hunsicker LG, Lewis JB, et al. Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy[summary for patients in Ann Intern Med. 2003 Apr 1;138(7):I43; PMID: 12667050]. Ann Intern Med 2003;138(7):542–9.

Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345(12):861–9.

Carr AA, Kowey PR, Devereux RB, et al. Hospitalizations for new heart failure among subjects with diabetes mellitus in the RENAAL and LIFE studies. Am J Cardiol 2005;96(11):1530–6.

Chapman N, Huxley R, Anderson C, et al. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial. Stroke 2004;35(1):116–21.

Cocco G, Ettlin T, Baumeler HR. The effect of amlodipine and enalapril on blood pressure and neurohumoral activation in hypertensive patients with Ribbing's disease (multiple epiphysal dystrophy). Clin Cardiol 2000;23(2):109–14.

Contreras G, Greene T, Agodoa LY, et al. Blood pressure control, drug therapy, and kidney disease. Hypertension 2005;46(1):44–50.

Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311):995–1003.

Davis BR, Piller LB, Cutler JA, et al. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation 2006;113(18):2201–10.

De Cesaris R, Ranieri G, Filitti V, et al. Effects of atenolol and enalapril on kidney function in hypertensive diabetic patients. J Cardiovasc Pharmacol 1993;22(2):208–14.

Derosa G, Ragonesi PD, Mugellini A, et al. Effects of telmisartan compared with eprosartan on blood pressure control, glucose metabolism and lipid profile in hypertensive, type 2 diabetic patients: a randomized, double-blind, placebo-controlled 12-month study. Hypertens Res 2004;27(7):457–64.

Devereux RB, Dahlof B, Kjeldsen SE, et al. Effects of losartan or atenolol in hypertensive patients without clinically evident vascular disease: a substudy of the LIFE randomized trial. Ann Intern Med 2003;139(3):169–77.

Douglas JG, Agodoa L. ACE inhibition is effective and renoprotective in hypertensive nephrosclerosis: the African American Study of Kidney Disease and Hypertension (AASK) trial. Kidney Int Suppl 2003;(83):S74–6.

Ecder T, Chapman AB, Brosnahan GM, et al. Effect of antihypertensive therapy on renal function and urinary albumin excretion in hypertensive patients with autosomal dominant polycystic kidney disease. Am J Kidney Dis 2000;35(3):427–32.

Fogari R, Preti P, Zoppi A, et al. Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients. Am J Hypertens 2002;15(12):1042–9.

Fossum E, Moan A, Kjeldsen SE, et al. The effect of losartan versus atenolol on cardiovascular morbidity and mortality in patients with hypertension taking aspirin: the Losartan Intervention for Endpoint Reduction in hypertension (LIFE) study. J Am Coll Cardiol 2005;46(5):770–5.

Gray A, Clarke P, Raikou M, et al. An economic evaluation of atenolol vs. captopril in patients with Type 2 diabetes (UKPDS 54). Diabet Med 2001;18(6):438–44.

Hansson L. Effects of angiotensin-converting enzyme inhibition versus conventional antihypertensive therapy on the glomerular filtration rate. Cardiology 1995;86 Suppl 1:30–3.

Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999;354(9192):1751–6.

Himmelmann A, Hansson L, Hansson BG, et al. ACE inhibition preserves renal function better than beta-blockade in the treatment of essential hypertension. Blood Press 1995;4(2):85–90.

Himmelmann A, Hansson L, Hansson BG, et al. Long-term renal preservation in essential hypertension. Angiotensin converting enzyme inhibition is superior to beta-blockade. Am J Hypertens 1996;9(9):850–3.

Hoieggen A, Alderman MH, Kjeldsen SE, et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004;65(3):1041–9.

Ibsen H, Wachtell K, Olsen MH, et al. Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy. J Hypertens 2004;22(9):1805–11.

Iino Y, Hayashi M, Kawamura T, et al. Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study. Clin Exp Nephrol 2003;7(3):221–30.

Iino Y, Hayashi M, Kawamura T, et al. Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension--a report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) study. Hypertens Res 2004;27(1):21–30.

Julius S, Alderman MH, Beevers G, et al. Cardiovascular risk reduction in hypertensive black patients with left ventricular hypertrophy: the LIFE study. J Am Coll Cardiol 2004;43(6):1047–55.

Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363(9426):2022–31.

Kizer JR, Dahlof B, Kjeldsen SE, et al. Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the Losartan Intervention For Endpoint reduction in hypertension study. Hypertension 2005;45(1):46–52.

Kjeldsen SE, Dahlof B, Devereux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA 2002;288(12):1491–8.

Kumagai H, Hayashi K, Kumamaru H, et al. Amlodipine is comparable to angiotensin-converting enzyme inhibitor for long-term renoprotection in hypertensive patients with renal dysfunction: a one-year, prospective, randomized study. Am J Hypertens 2000;13(9):980–5.

Kuperstein R, Sasson Z. Effects of antihypertensive therapy on glucose and insulin metabolism and on left ventricular mass: A randomized, double-blind, controlled study of 21 obese hypertensives. Circulation 2000;102(15):1802–6.

Lakshman MR, Reda DJ, Materson BJ, et al. Diuretics and beta-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Arch Intern Med 1999;159(6):551–8.

Lea J, Greene T, Hebert L, et al. The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease: results of the African American study of kidney disease and hypertension. Arch Intern Med 2005;165(8):947–53.

Lewis CE, Grandits A, Flack J, et al. Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension. Results of the Treatment of Mild Hypertension Study. Arch Intern Med 1996;156(4):377–85.

Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345(12):851–60.

Lindholm LH, Ibsen H, Borch-Johnsen K, et al. Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens 2002;20(9):1879–86.

Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311):1004–10.

Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21(5):875–86.

Lithell H, Hansson L, Skoog I, et al. The Study on COgnition and Prognosis in the Elderly (SCOPE); outcomes in patients not receiving add-on therapy after randomization. J Hypertens 2004;22(8):1605–12.

Malmqvist K, Ohman KP, Lind L, et al. Long-term effects of irbesartan and atenolol on the renin-angiotensin-aldosterone system in human primary hypertension: the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA). J Cardiovasc Pharmacol 2003;42(6):719–26.

Massie BM. What is the meaning of LIFE? Implications of the Losartan Intervention for Endpoint reduction in hypertension trial for heart failure physicians. J Card Fail 2002;8(4):197–201.

Neaton JD, Grimm RH Jr, Prineas RJ, et al. Treatment of Mild Hypertension Study. Final results. Treatment of Mild Hypertension Study Research Group. JAMA 1993;270(6):713–24.

Nielsen FS, Rossing P, Gall MA, et al. Impact of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes 1994;43(9):1108–13.

Nielsen FS, Rossing P, Gall MA, et al. Long-term effect of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes 1997;46(7):1182–8.

Olsen MH, Fossum E, Hoieggen A, et al. Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy. J Hypertens 2005;23(4):891–8.

Papademetriou V, Farsang C, Elmfeldt D, et al. Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE). J Am Coll Cardiol 2004;44(6):1175–80.

Patel V, Rassam SM, Chen HC, et al. Effect of angiotensin-converting enzyme inhibition with perindopril and beta-blockade with atenolol on retinal blood flow in hypertensive diabetic subjects. Metabolism 1998;47(12 Suppl 1):28–33.

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