MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension

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Medical Education Library

MODULE 1: Historical Review of Evidence-Based Treatment of Hypertension

August 2012 · Vol. 61, No. 08 Suppl: S5-S14

References

1. Hamdy RC. Hypertension: a turning point in the history of medicine…and mankind. South Med J. 2001;94(11):1045-1047.

2. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202(11):1028-1034.

3. Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA. 1979;242(23):2562-2571.

4. Amery A, De Schaepdryver A. The European Working Party on High Blood Pressure in the Elderly. Am J Med. 1991;90(3A):1S-4S.

5. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J (Clin Res Ed). 1985;291(6488):97-104.

6. The Australian therapeutic trial in mild hypertension. Report by the Management Committee. Lancet. 1980;1(8181):1261-1267.

7. Wilhelmsen L, Berglund G, Elmfeldt D, et al. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. J Hypertens. 1987;5(5):561-572.

8. Wikstrand J, Berglund G, Tuomilehto J. Beta-blockade in the primary prevention of coronary heart disease in hypertensive patients. Review of present evidence. Circulation. 1991;84(6 Suppl):VI93-VI100.

9. Wikstrand J, Warnold I, Tuomilehto J, et al. Metoprolol versus thiazide diuretics in hypertension. Morbidity results from the MAPHY Study. Hypertension. 1991;17(4):579-588.

10. Olsson G, Tuomilehto J, Berglund G, et al. Primary prevention of sudden cardiovascular death in hypertensive patients. Mortality results from the MAPHY Study. Am J Hypertens. 1991;4(2 Pt 1):151-1511.

11. SHEP Cooperative 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(24):3255-3264.

12. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ. 1992;304(6824):405-412.

13. Dahlöf B, Lindholm LH, Hansson L, Scherstén B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991;338(8778):1281-1285.

14. Neaton JD, Grimm RH, Jr, Prineas RJ, et al. Treatment of Mild Hypertension Study Research Group. Treatment of Mild Hypertension Study. Final results. JAMA. 1993;270(6):713-724.

15. Materson BJ, Reda DJ, Cushman WC, et al. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo [published correction appears in N Engl J Med. 1994;330(23):1689]. N Engl J Med. 1993;328(13):914-921.

16. Hansson L, Zanchetti A, Carruthers SG, et al. HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351(9118):1755-1762.

17. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [published correction appears in BMJ. 1999;318(7175):29]. BMJ. 1998;317(7160):703-713.

18. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317(7160):713-720.

19. Staessen JA, Fagard R, Thijs L, et al. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350(9080):757-764.

20. Liu L, Wang JG, Gong L, Liu G, Staessen JA. Systolic Hypertension in China (Syst-China) Collaborative Group. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. J Hypertens. 1998;16(12 Pt 1):1823-1829.

21. Hansson L, Hedner T, Lindholm L, et al. The Captopril Prevention Project (CAPPP) in hypertension—baseline data and current status. Blood Press. 1997;6(6):365-367.

22. 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):1751-1756.

23. Brown MJ, Palmer CR, Castaigne A, 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) [published correction appears in Lancet. 2000;356(9228):514]. Lancet. 2000;356(9227):366-372.

24. Hansson L, Hedner T, Lund-Johansen P, 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(9227):359-365.

25. Lithell H, Hansson L, Skoog I, et al. SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21(5):875-886.

26. Black HR, Elliott WJ, Grandits G, et al. CONVINCE Research Group. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289(16):2073-2082.

27. 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) [published corrections appear in JAMA. 2003;289(2):178; JAMA. 2004;291(18):2196]. JAMA. 2002;288(23):2981-2997.

28. Wing LM, Reid CM, Ryan P, et al. Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting– enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348(7):583-592.

29. Dahlöf B, Devereux RB, Kjeldsen SE, et al. LIFE Study Group. 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.

30. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-1559.

31. Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet. 2004;363(9426):2049-2051.

32. Dahlöf B, Sever PS, Poulter NR, et al. ASCOT Investigators. 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(9489):895-906.

33. Jamerson K, Bakris GL, Dahlöf B, et al. ACCOMPLISH Investigators. Exceptional early blood pressure control rates: the ACCOMPLISH trial. Blood Press. 2007;16(2):80-86.

34. Julius S, Nesbitt SD, Egan BM, et al. Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354(16):1685-1697.

35. ATMOSPHERE study, [NCT00853658] ongoing trial. Trial-Results Center Web site. http://www.trialresultscenter.org/study9503-ATMOSPHERE.htm. Accessed March 28, 2012.

36. Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant. 2009;24(5):1663-1671.

37. Massie BM, Carson PE, McMurray JJ, et al. I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359(23):2456-2467.

38. US National Library of Medicine. The Edward D. Freis Papers: the VA Cooperative Study and the Beginning of Routine Hypertension Screening, 1964-1980. http://profiles.nlm.nih.gov/ps/retrieve/Narrative/XF/p-nid/172. Accessed March 26, 2012.

39. Comberg HU, Heyden S, Knowles M, et al. Long-term survey of 450 hypertensives of the HDFP. Munch Med Wochenschr. 1991;133:32-38.

40. Skoog I, Lithell H, Hansson L, et al. SCOPE Study Group. Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes: Study on COgnition and Prognosis in the Elderly (SCOPE). Am J Hypertens. 2005;18(8):1052-1059.

41. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Coll Cardiol. 2011;57(20):2037-2114.

42. Beckett NS, Peters R, Fletcher AE, et al. HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-1898.

43. Weber MA, Neutel JM, Frishman WH. Combination drug therapy. In: Frishman WH, Sonnenblick EH, Sica DA, eds. Cardiovascular Pharmacotherapeutics. 2nd ed. New York, NY: McGraw-Hill; 2003:355–368.

44. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil- Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290(21):2805-2816.

45. Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension. 2007;50(2):299-305.

46. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122(3):290-300.

47. Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens. 2010;4(2):90-98.

48. Weir MR, Levy D, Crikelair N, Rocha R, Meng X, Glazer R. Time to achieve blood-pressure goal: influence of dose of valsartan monotherapy and valsartan and hydrochlorothiazide combination therapy. Am J Hypertens. 2007;20(7):807-815.

49. National Heart, . Lung, and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. http://www.nhlbi.nih.gov/guidelines/hypertension/. Published 2003. Accessed March 27, 2012.

50. National Institute for Health and Clinical Excellence. Hypertension: Clinical management of primary hypertension in adults. http://www.nice.org.uk/nicemedia/live/13561/56008/56008.pdf. Published August 2011. Accessed March 27, 2012.

Given that hypertension is far more common in older people who have increased rates of hypertensive target organ damage or CV disease (CVD), researchers have focused on the effects of antihypertensive therapy in this population for some time.⁴¹ Sentinel studies in this population include the European Working Party on High Blood Pressure in the Elderly (EWPHPE) study,⁴ the Medical Research Council trial of treatment of hypertension in older adults (MRC-2),¹² the Swedish Trial in Old Patients with Hypertension-2 (STOP-2),²² the Study on Cognition and Prognosis in the Elderly (SCOPE),²⁵ the Systolic Hypertension in the Elderly Program (SHEP) study,¹¹ the Systolic Hypertension in Europe (Syst-Eur) study,¹⁹ and the Systolic Hypertension in China (Syst-China) study.²⁰ The key outcomes of these trials are shown in TABLE 1. In general, these trials have shown that antihypertensive therapy has a marked benefit in a shorter period of time in older patients than in younger patients, particularly in terms of reduced stroke and CHF rates.

The Hypertension in the Very Elderly Trial (HYVET), which enrolled participants 80 years of age and older, demonstrated that reducing systolic BP (SBP) from 170 mm Hg to 145 mm Hg with indapamide sustained release 1.5 mg and perindopril 2 to 4 mg as needed reduced all-cause deaths 21% (P =.02), stroke-related deaths 39% (P =.05), and fatal and nonfatal heart failure (HF) 64% (P < .001), compared with placebo.⁴² The intervention group also experienced a 34% reduction in all CV events (P < .001) and a 30% reduction in stroke (P =.055).⁴² However, there is still no good evidence that reducing BP further in this population provides additional benefits over the concomitant risks.

In the 1980s, numerous trials were developed to address the question: “What is the best way to treat high BP?” These included the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial,⁷ the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) study,^8-10 the Treatment of Mild Hypertension Study (TOMHS),¹⁴ and the VA Cooperative Study on single drug therapy.¹⁵

Subsequently, several trials were conducted that focused on the safety of calcium antagonists for the primary or background treatment of hypertension. These included the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Treatment (INSIGHT),²³ the Nordic Diltiazem (NORDIL) study,²⁴ the Australian National Blood Pressure Study 2 (ANBP2),²⁸ the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial,²⁶ the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial,²⁹ and the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) study.³⁷

These studies, conducted from the mid 1990s to the present, have shown that calcium antagonists, including amlodipine, diltiazem, nifedipine, and verapamil, are as effective as thiazide-type diuretics or beta-blockers in preventing CV events in patients with hypertension. Further, the LIFE trial demonstrated that the angiotensin II receptor blocker (ARB) losartan was more effective than the beta-blocker atenolol in reducing stroke events and that blockade of the renin- angiotensin system did not seem to affect CV outcomes in patients with HF with preserved systolic function, a common problem in patients with prolonged hypertension and left ventricular hypertrophy.²⁹

The largest randomized, double-blind, antihypertensive trial performed to date is the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). It involved 33,357 participants 55 years of age and older with hypertension and at least 1 other coronary heart disease (CHD) risk factor.²⁷ Participants were randomized to chlorthalidone, amlodipine, doxazosin, or lisinopril. The doxazosin arm was discontinued early because an increase in CV events was observed after 2 years, relative to the other treatment arms. At follow-up (mean, 4.9 years), there was no difference between the 3 groups in terms of the primary outcome (combined fatal CHD or nonfatal myocardial infarction [MI], analyzed by intent-to-treat) or all-cause mortality.²⁷ Of note, 5-year SBP levels were higher in the amlodipine (0.8 mm Hg, P=.03) and lisinopril (2 mm Hg, P < .001) groups than in the chlorthalidone group, whereas the 5-year DBP levels were significantly lower in the amlodipine group (0.8 mm Hg, P < .001).²⁷

Secondary analyses showed a higher 6-year rate of HF development in the amlodipine group than in the chlorthali-done group (10.2% vs 7.7%; relative risk [RR], 1.38; 95% con- fidence interval [CI], 1.25-1.52), whereas the lisinopril group had a higher 6-year rate of combined CVD (33.3% vs 30.9%; RR, 1.10; 95% CI, 1.05-1.16), stroke (6.3% vs 5.6%; RR, 1.15; 95% CI, 1.02-1.30), and HF (8.7% vs 7.7%; RR, 1.19; 95% CI, 1.07-1.31) than the chlorthalidone group. The design of ALLHAT led to worsened control of BP in African Americans relative to white patients who were receiving lisinopril, which may have been an important factor in the subsequent increased rate of stroke in African American patients who were receiving lisinopril rather than chlorthalidone.²⁷