Blood Pressure-Lowering Treatment and the Prevention of Heart Failure: Differences and Similarities of Antihypertensive Drug Classes

  • Costas ThomopoulosEmail author
  • Alberto Zanchetti
Part of the Updates in Hypertension and Cardiovascular Protection book series (UHCP)


Benefit of blood pressure (BP)-lowering treatment on various outcomes was evaluated by meta-analyses restricted to randomized controlled trials (RCTs) measuring all major outcomes. The question whether BP-lowering and each class of antihypertensive agents prevent “new-onset” heart failure was explored by additional meta-analyses limited to RCTs excluding baseline heart failure from randomization. Thirty-five BP-lowering RCTs measured all outcomes, and heart failure [RR 0.63 (0.52–0.75)] and stroke [RR 0.58 (0.49–0.68)] were the outcomes most effectively prevented. Heart failure and stroke reductions were significantly related to systolic BP, diastolic BP, and pulse pressure reductions. In 18 BP-lowering RCTs excluding baseline heart failure from recruitment, heart failure reduction (“new-onset” heart failure) [RR 0.58 (0.44–0.75)] was very similar to that observed in the entire set of RCTs. In meta-analyses of head-to-head comparisons of different antihypertensive classes, calcium antagonists were inferior in preventing “new-onset” heart failure [RR 1.16 (1.01–1.33)]. However, this inferiority disappeared when meta-analysis was limited to RCTs allowing concomitant use of diuretics, beta-blockers, or renin-angiotensin system blockers, also in the calcium antagonist group [RR 0.96 (0.81–1.12)]. BP-lowering treatment effectively prevents “new-onset” heart failure. It is suggested that BP lowering by calcium antagonists is effective as BP lowering by other drugs in preventing “new-onset” heart failure, unless the trial design creates an unbalance against calcium antagonists.


Blood pressure-lowering trials Cardiovascular death Coronary heart disease Heart failure Hypertension Meta-analysis Randomized controlled trials Stroke 



The data, concepts, and figures reported in this chapter are largely taken from an original article published by the authors in the Journal of Hypertension [3]. Wolters Kluwer Health, Inc., is thanked for permission.


  1. 1.
    Moser M, Hebert PR. Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. J Am Coll Cardiol. 1996;27:1214–8.CrossRefGoogle Scholar
  2. 2.
    Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta-analyses and meta-regression analyses of randomized trials. J Hypertens. 2014;32:2285–95.CrossRefGoogle Scholar
  3. 3.
    Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering treatment. 6. Prevention of heart failure and new-onset heart failure—meta-analyses of randomized trials. J Hypertens. 2016;34:373–84.CrossRefGoogle Scholar
  4. 4.
    Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomized controlled trial. Lancet. 2004;364:849–57.CrossRefGoogle Scholar
  5. 5.
    Management Committee. The Australian therapeutic trial in mild hypertension. Lancet. 1980;315:1261–7.CrossRefGoogle Scholar
  6. 6.
    Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004;292:2217–25.CrossRefGoogle Scholar
  7. 7.
    Amery A, Brixko P, Clement D, De Schaepdryver A, Fagard R, Forte J, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet. 1985;325:1349–54.CrossRefGoogle Scholar
  8. 8.
    Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. BMJ. 1986;293:1145–51.CrossRefGoogle Scholar
  9. 9.
    Hypertension-Stroke Cooperative Study Group. Effect of antihypertensive treatment on stroke recurrence. JAMA. 1974;229:409–18.CrossRefGoogle Scholar
  10. 10.
    Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887–98.CrossRefGoogle Scholar
  11. 11.
    Helgeland A. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. Am J Med. 1980;69:725–32.CrossRefGoogle Scholar
  12. 12.
    Liu L, Wang JG, Gong L, Liu G, Staessen JA. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. Systolic hypertension in China (Syst-China) collaborative group. J Hypertens. 1998;16:1823–9.CrossRefGoogle Scholar
  13. 13.
    Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757–64.CrossRefGoogle Scholar
  14. 14.
    Smith WM. Treatment of mild hypertension: results of a ten-year intervention trial. Circ Res. 1977;40:I98–105.CrossRefGoogle Scholar
  15. 15.
    JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res. 2008;31:2115–27.CrossRefGoogle Scholar
  16. 16.
    UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J. 1998;317:703–13.CrossRefGoogle Scholar
  17. 17.
    Marre M, Lievre M, Chatellier G, Mann JF, Passa P, Ménard J, DIABHYCAR Study Investigators. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). Br Med J. 2004;328:495.CrossRefGoogle Scholar
  18. 18.
    DREAM Trial Investigators. Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the diabetes REduction assessment with ramipril and rosiglitazone medication (DREAM) trial. Diabetes Care. 2008;31:1007–14.CrossRefGoogle Scholar
  19. 19.
    The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–53.CrossRefGoogle Scholar
  20. 20.
    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.CrossRefGoogle Scholar
  21. 21.
    Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174–83.CrossRefGoogle Scholar
  22. 22.
    ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;37:829–40.Google Scholar
  23. 23.
    Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A. The Felodipine event reduction (FEVER) study: a randomized long-term placebo controlled trial in Chinese hypertensive patients. J Hypertens. 2005;23:2157–72.CrossRefGoogle Scholar
  24. 24.
    Perry HM Jr, Smith WM, McDonald RH, Black D, Cutler JA, Furberg CD, et al. Morbidity and mortality in the systolic hypertension in the elderly program (SHEP) pilot study. Stroke. 1989;20:4–13.CrossRefGoogle Scholar
  25. 25.
    SHEP Co-operative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the systolic hypertension in the elderly program (SHEP). JAMA. 1991;265:3255–64.CrossRefGoogle Scholar
  26. 26.
    Dahlöf B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-hypertension). Lancet. 1991;338:1281–5.CrossRefGoogle Scholar
  27. 27.
    Verdecchia P, Staessen JA, Angeli F, De Simone G, Achilli A, Ganau A, et al. Usual vs. tight control of systolic blood pressure in nondiabetic patients with hypertension (cardio-sis): an open-label randomized trial. Lancet. 2009;374:525–33.CrossRefGoogle Scholar
  28. 28.
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.CrossRefGoogle Scholar
  29. 29.
    The NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362:1477–90.CrossRefGoogle Scholar
  30. 30.
    Imai E, Chan JC, Ito S, Yamasaki T, Kobayashi F, Haneda M, Makino H for the ORIENT Study Investigators. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia. 2011;54:2978–86.CrossRefGoogle Scholar
  31. 31.
    The PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058–68.CrossRefGoogle Scholar
  32. 32.
    Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension. 5. Head-to-head comparisons of various classes of antihypertensive drugs—overview and meta-analyses. J Hypertens. 2015;33:1321–41.CrossRefGoogle Scholar
  33. 33.
    Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417–28.CrossRefGoogle Scholar
  34. 34.
    ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. 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). JAMA. 2002;288:2981–97.CrossRefGoogle Scholar
  35. 35.
    Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, et al. A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348:583–92.CrossRefGoogle Scholar
  36. 36.
    Matsuzaki M, Ogihara T, Umemoto S, Rakugi H, Matsuoka H, Shimada K, et al. Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: a randomized controlled trial. J Hypertens. 2011;29:1649–59.CrossRefGoogle Scholar
  37. 37.
    Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000;356:366–72.CrossRefGoogle Scholar
  38. 38.
    Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA. 1996;276:785–91.CrossRefGoogle Scholar
  39. 39.
    National Intervention Cooperative Study in Elderly Hypertensives Study Group. Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. Hypertension. 1999;34:1129–33.CrossRefGoogle Scholar
  40. 40.
    Zanchetti A, Agabiti Rosei E, Dal Palù C, Leonetti G, Magnani B, Pessina A, et al. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens. 1998;16:1667–76.CrossRefGoogle Scholar
  41. 41.
    Wilhelmsen L, Berglund G, Elmfeldt D, Fitzsimons T, Holzgreve H, Hosie J, et al. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. J Hypertens. 1987;5:561–72.CrossRefGoogle Scholar
  42. 42.
    Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895–906.CrossRefGoogle Scholar
  43. 43.
    Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003.CrossRefGoogle Scholar
  44. 44.
    UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J. 1998;317:713–20.CrossRefGoogle Scholar
  45. 45.
    Ogihara T, Nakao K, Fukui T, Fukiyama K, Ueshima K, Oba K, et al. Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial. Hypertension. 2008;51:393–8.CrossRefGoogle Scholar
  46. 46.
    Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289:2073–82.CrossRefGoogle Scholar
  47. 47.
    Yui Y, Sumiyoshi T, Kodama K, Hirayama A, Nonogi H, Kanmatsuse K, et al. Comparison of nifedipine retard with angiotensin converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) randomized trial. Hypertens Res. 2004;27:181–91.CrossRefGoogle Scholar
  48. 48.
    Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet. 2000;356:359–65.CrossRefGoogle Scholar
  49. 49.
    Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645–52.CrossRefGoogle Scholar
  50. 50.
    Schrader J, Lüders S, Kulschewski A, Hammersen F, Plate K, Berger J, et al. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005;36:1218–26.CrossRefGoogle Scholar
  51. 51.
    Muramatsu T, Matsushita K, Yamashita K, Kondo T, Maeda K, Shintani S, et al. Comparison between valsartan and amlodipine regarding cardiovascular morbidity and mortality in hypertensive patients with glucose intolerance: NAGOYA HEART study. Hypertension. 2012;59:580–6.CrossRefGoogle Scholar
  52. 52.
    Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022–31.CrossRefGoogle Scholar
  53. 53.
    ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547–59.CrossRefGoogle Scholar
  54. 54.
    Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:611–6.CrossRefGoogle Scholar
  55. 55.
    Nakamura T, Kanno Y, Takenaka T, Suzuki H. Efficacy of candesartan on outcome in Saitama trial group. An angiotensin receptor blocker reduces the risk of congestive heart failure in elderly hypertensive patients with renal insufficiency. Hypertens Res. 2005;28:415–23.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of CardiologyHelena Venizelou HospitalAthensGreece
  2. 2.Scientific DirectionIstituto Auxologico Italiano IRCCSMilanItaly
  3. 3.Centro Interuniversitario di Fisiologia Clinica e IpertensioneUniversità degli Studi di MilanoMilanItaly

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