Editor-In-Chief: C. Michael Gibson, M.S., M.D.  Phone:617-632-7753; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S.
Patients diagnosed with syndrome X and hypertension may have microvascular angina characterized by a reduced coronary vasodilator reserve and increased sympathetic drive. ACE inhibition in such patients may attenuate sympathetic coronary vasoconstriction, normalize thallium perfusion defects and reduce exercise-induced ischemia with subsequent increased myocardial oxygen supply. Based on the recent AHA and ESC guidelines, the recommended goal blood pressure in patients with atherosclerotic coronary vascular disease is less than 130/80 mm Hg.
Mechanisms of Benefit
- The relative risk reduction for composite primary end-points with ACE inhibition was significant in the HOPE (26%; 95% CI 13–36) and EUROPA trials (14%; 95% CI 23 to 28); however, the PEACE study (5%; 95% CI 219 to 24) found no significant risk reduction. These differences in cardiovascular outcomes were attributed to the difference in non-study related therapies such as beta-blocker, CCBs or lipid-lowering agents received at baseline.
In comparison to other anti-hypertensive drugs, ACEIs although remain the standard drug of choice for hypertension and heart failure, it has not been shown to confer overall protection against cardiovascular complications.
Supportive Trial Data Demonstrating Significant Benefit with the use of ACEIs or ARBs
- In the HOPE trial, 9,297 high-risk patients with evidence of vascular disease or diabetes plus one other cardiovascular risk factor in the absence of heart failure were randomized to receive either ramipril (10 mg/day) or placebo. The goal of the trial was to assess the role of angiotensin-converting-enzyme inhibitor in the management of patients who were at increased risk for cardiovascular events and with preserved left ventricular function. The primary end-points from cardiovascular causes of mortality (6.1% in the ramipril group vs. 8.1% in the placebo group; relative risk, 0.74; P<0.001), non-fatal MI (9.9% vs. 12.3%; relative risk, 0.80; P<0.001), stroke (3.4% vs. 4.9%; relative risk, 0.68; P<0.001) and complications related to diabetes (6.4% vs. 7.6%; relative risk, 0.84; P=0.03) were significantly reduced in the ramipril group as observed during a mean follow-up time of 5 years. The 22% relative risk reduction in cardiovascular death, myocardial infarction, or stroke observed with ramipril was independent of other therapies such as aspirin, beta-blockers and anti-lipid agents. Thus, the study was prematurely terminated after a 5-year follow-up, as ramipril was associated with a significant reduction in the mortality, MI and stroke in high-risk patients with preserved ejection fraction.
- In a sub-study, that hypothesized the benefits of ramipril use was not confined to the reduction in blood pressure alone, researchers calculated the blood-pressure-related risk estimates from the placebo group of the HOPE trial and from earlier studies. The study concluded that the benefits associated with ramipril were additive in patients with normal or higher than normal baseline blood pressure.
- In another substudy, that assessed the comparative effects of ramipril on ambulatory (ABP) and office blood pressures (OBP), researchers observed that ramipril did not significantly reduce the OBP (8/2 mm Hg, P=not significant) or ABP (6/2 mm Hg, P=not significant) after 1 year. However, the 24-hour ABP was significantly reduced (10/4 mm Hg, P=0.03), as a consequent of a more pronounced blood pressure lowering effect occurring during nighttime (17/8 mm Hg, P<0.001).
- In the EUROPA trial, 13,655 patients with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test (5%), were randomized to receive either perindopril (8 mg/day) or placebo. The goal of the study was to assess the effect of ACE inhibition in the reduction of cardiovascular risk in patients with stable coronary artery disease in the absence of heart failure. The study designs of both the HOPE and EUROPA trials were similar; however, the EUROPA trial involved patients with lower rates of hypertension, diabetes and peripheral artery disease (27% in the EUROPA trial vs. 47% in the HOPE trial). Approximately, a 20% relative reduction in the primary endpoint of all cardiovascular causes of mortality including MI or cardiac arrest during a mean follow-up of 4.2 years was observed in the perindopril group (8% vs. 10%, 95% CI 9-29, p=0.0003). Thus, the study concluded that in patients with stable coronary heart disease without apparent heart failure, perindopril significantly improved outcomes.
- In the CAMELOT trial, 1991 patients with angiographically documented CAD and diastolic blood pressure less than 100 mm Hg, were randomized to receive either amlodipine (10mg), enalapril (20 mg), or placebo; to compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. The mean baseline blood pressure was 129/78 mm Hg and both amlodipine and enalapril caused significant reductions in the blood pressure (4.8/2.5 and 4.9/2.4 vs. 0.7/0.6 mmHg; p<0.001 for both vs. placebo). At 1-year follow-up, a 16% significant reduction in the primary end-point of all cardiovascular causes of mortality and incidence of cardiovascular events was observed in the amlodipine group (hazard ratio 0.69; 95% CI, 0.54-0.88; p=0.003). However, no significant difference was observed with the other two groups: 23.1% in the placebo group and 20.2% in the enalapril group (hazard ratio 0.85; 95% CI, 0.67-1.07; p=0.16). Thus, the study concluded in patients with CAD and normal blood pressure, the administration of amlodipine resulted in reduced cardiovascular events; however, similar smaller and non-significant benefits were observed with enalapril.
- The IVUS substudy, involving 274 patients with normal blood pressure at baseline, reported a significant correlation between the progression of atherosclerosis and the reduction in blood pressure with the administration of amlodipine.
- The VALUE study, involving 15,245 hypertensive patients with high cardiovascular risk (46% patients had CAD) who were randomized to receive either amlodipine or valsartan. At 4.2 year follow-up, no significant difference in the primary composite endpoint was observed between the two groups. Thus, the study emphasized the importance of prompt blood pressure control to reduce the incidence of cardiac mortality and morbidity, irrespective of the type of anti-hypertensive agent being used.
- A recent 2011 meta-analysis, reviewed 25 randomized controlled trials involving 63,000 patients to evaluate the effect of anti-hypertensive agents such as ACEIs, ARBs, beta-blockers, calcium channel blockers on the secondary prevention of cardiovascular events and all-cause mortality among patients without clinically defined hypertension. The relative risk ratios in comparison to control group was: 0.85 for composite cardiovascular events, 0.83 for cardiovascular mortality, 0.87 for all-cause mortality, 0.80 for MI, 0.71 for CHF and 0.77 for stroke, with the corresponding ARR per 1000 persons treated was -27.1 (95% CI, -40.3 to -13.9) for composite cardiovascular events, -15.4 (95% CI, -32.5 to 1.7) for cardiovascular mortality, -13.7 (95% CI, -24.6 to -2.8) for all-cause mortality, -13.3 (95% CI, -28.4 to 1.7) for MI, -43.6 (95% CI, -65.2 to -22.0) for CHF and -7.7 (95% CI, -15.2 to -0.3) for stroke. Thus, the study concluded that in patients with documented cardiovascular disease without hypertension, there was a significant reduction in the risk of composite cardiovascular events and all-cause mortality associated with anti-hypertensive therapy. Researchers suggested that no specific benefit was achieved with the use of ACEIs or ARBs in comparison to other anti-hypertensive agents.
Supportive Trial Data Demonstrating No Benefit with the use of ACEIs or ARBs
- In the CHARM-preserved study, 3023 patients with class II-IV CHF and LVEF greater than 40% at baseline were randomized to receive either candesartan (32 mg/day) or placebo. Researchers assessed the effect of addition of an ARB to the current regimen. It was reported that the primary end-point of cardiovascular causes of mortality during a median follow-up of 36.6 months did not differ significantly between the two groups: 22% in the candesartan group and 24% in the placebo group (p=0.118). Thus, the study reported no significant benefit observed with the use of candesartan in patients with preserved LV function.
2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines and the 2002 Guideline Update for the Management of Patients With Chronic Stable Angina (DO NOT EDIT) 
Renin-Angiotensin-Aldosterone Receptor Blockers (DO NOT EDIT)
ESC Guidelines- Pharmacological Therapy to Improve Prognosis in Patients with Stable Angina (DO NOT EDIT)
Renin-Angiotensin-Aldosterone Receptor Blockers (DO NOT EDIT)
- ↑ 1.0 1.1 Kaski JC, Rosano G, Gavrielides S, Chen L (1994) Effects of angiotensin-converting enzyme inhibition on exercise-induced angina and ST segment depression in patients with microvascular angina. J Am Coll Cardiol 23 (3):652-7. PMID: 8113548
- ↑ 2.0 2.1 van den Heuvel AF, Dunselman PH, Kingma T, Verhorst P, Boomsma F, van Gilst WH et al. (2001) Reduction of exercise-induced myocardial ischemia during add-on treatment with the angiotensin-converting enzyme inhibitor enalapril in patients with normal left ventricular function and optimal beta blockade. J Am Coll Cardiol 37 (2):470-4. PMID: 11216965
- ↑ 3.0 3.1 3.2 Fraker TD, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J et al. (2007)2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 116 (23):2762-72. PMID: 17998462
- ↑ 4.0 4.1 4.2 Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F; et al. (2006). [url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367  "Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology"]. Eur Heart J. 27 (11): 1341–81. doi:10.1093/eurheartj/ehl001. PMID 16735367.
- ↑ Rosendorff C, Black HR, Cannon CP, Gersh BJ, Gore J, Izzo JL et al. (2007) Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 115 (21):2761-88. DOI:10.1161/CIRCULATIONAHA.107.183885 PMID: 17502569
- ↑ Lewington S, Clarke R, Qizilbash N, Peto R, Collins R, Prospective Studies Collaboration (2002) Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360 (9349):1903-13. PMID: 12493255
- ↑ 7.0 7.1 Turnbull F, Blood Pressure Lowering Treatment Trialists' Collaboration (2003) Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 362 (9395):1527-35. PMID: 14615107
- ↑ 8.0 8.1 Staessen JA, Wang JG, Thijs L (2003) Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 21 (6):1055-76. DOI:10.1097/01.hjh.0000059044.65882.db PMID: 12777939
- ↑ 9.0 9.1 Dagenais GR, Yusuf S, Bourassa MG, Yi Q, Bosch J, Lonn EM et al. (2001) Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation 104 (5):522-6. PMID: 11479247
- ↑ 10.0 10.1 10.2 Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators (2003) Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 362 (9386):782-8. PMID: 13678872
- ↑ 11.0 11.1 11.2 Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J et al. (2004) Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 351 (20):2058-68. DOI:10.1056/NEJMoa042739 PMID: 15531767
- ↑ Luft FC (2001) Recent clinical trial highlights in hypertension. Curr Hypertens Rep 3 (2):133-8. PMID: 11276395
- ↑ 13.0 13.1 European Society of Hypertension-European Society of Cardiology Guidelines Committee (2003)2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 21 (6):1011-53.DOI:10.1097/01.hjh.0000059051.65882.32PMID: 12777938
- ↑ 14.0 14.1 14.2 American Diabetes Association (2003) Standards of medical care for patients with diabetes mellitus. Diabetes Care 26 Suppl 1 ():S33-50. PMID: 
- ↑ Faggiotto A, Paoletti R (1999) State-of-the-Art lecture. Statins and blockers of the renin-angiotensin system: vascular protection beyond their primary mode of action. Hypertension 34 (4 Pt 2):987-96. PMID: 10523396
- ↑ Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CR et al. (1994) Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 90 (4):2056-69. PMID: 7923694
- ↑ 17.0 17.1 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342 (3):145-53. DOI:10.1056/NEJM200001203420301 PMID: 10639539
- ↑ 18.0 18.1 Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ et al. (2003) Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 362 (9386):777-81. DOI:10.1016/S0140-6736(03)14285-7 PMID: 13678871
- ↑ Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH et al. (2003) Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 289 (19):2534-44. DOI:10.1001/jama.289.19.2534 PMID: 12759325
- ↑ Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B et al. (2002) Use of ramipril in preventing stroke: double blind randomised trial. BMJ 324 (7339):699-702. PMID: 11909785
- ↑ Lonn E, Roccaforte R, Yi Q, Dagenais G, Sleight P, Bosch J et al. (2002) Effect of long-term therapy with ramipril in high-risk women. J Am Coll Cardiol 40 (4):693-702. PMID: 12204499
- ↑ (2000) Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 355 (9200):253-9. PMID: 10675071
- ↑ Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J et al. (2001) Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet 358 (9299):2130-1. DOI:10.1016/S0140-6736(01)07186-0 PMID: 11784631
- ↑ Svensson P, de Faire U, Sleight P, Yusuf S, Ostergren J (2001) Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE Substudy. Hypertension 38 (6):E28-32. PMID: 11751742
- ↑ Daly CA, Fox KM, Remme WJ, Bertrand ME, Ferrari R, Simoons ML et al. (2005) The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J 26 (14):1369-78. DOI:10.1093/eurheartj/ehi225 PMID: 15860521
- ↑ Brugts JJ, Boersma E, Chonchol M, Deckers JW, Bertrand M, Remme WJ et al. (2007) The cardioprotective effects of the angiotensin-converting enzyme inhibitor perindopril in patients with stable coronary artery disease are not modified by mild to moderate renal insufficiency: insights from the EUROPA trial. J Am Coll Cardiol 50 (22):2148-55. DOI:10.1016/j.jacc.2007.08.029 PMID: 18036453
- ↑ 27.0 27.1 Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D et al. (2004) Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 292 (18):2217-25. DOI:10.1001/jama.292.18.2217 PMID: 15536108
- ↑ Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L et al. (2004) Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 363 (9426):2022-31. DOI:10.1016/S0140-6736(04)16451-9 PMID: 15207952
- ↑ Califf RM, Lokhnygina Y, Velazquez EJ, McMurray JJ, Leimberger JD, Lewis EF et al. (2009) Usefulness of beta blockers in high-risk patients after myocardial infarction in conjunction with captopril and/or valsartan (from the VALsartan In Acute Myocardial Infarction [VALIANT trial).] Am J Cardiol 104 (2):151-7. DOI:10.1016/j.amjcard.2009.03.020 PMID: 19576338
- ↑ Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA (2011) Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA 305 (9):913-22. DOI:10.1001/jama.2011.250 PMID: 21364140
- ↑ Gustafsson I, Torp-Pedersen C, Køber L, Gustafsson F, Hildebrandt P (1999) Effect of the angiotensin-converting enzyme inhibitor trandolapril on mortality and morbidity in diabetic patients with left ventricular dysfunction after acute myocardial infarction. Trace Study Group. J Am Coll Cardiol 34 (1):83-9. PMID: 10399995
- ↑ 32.0 32.1 Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS et al. (2003) ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 107 (1):149-58. PMID: 12515758