Chronic stable angina treatment angiotensin converting enzyme inhibitors (ACEI) and renin angiotensin aldosterone system blockers (RAAS blockers)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5] Phone:617-632-7753; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S.

Overview

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.

ACEI/RAAS Blockers

Mechanisms of Benefit

• ACE inhibition in patients with syndrome X and hypertension may attenuate sympathetic coronary vasoconstriction and reduce exercise-induced ischemia with subsequent increased myocardial oxygen supply.

• In one meta-analysis, researchers found that high blood pressure was strongly and directly related to overall mortality. Therefore, lowering blood pressure provides a greater benefit in the reduction of cardiovascular mortality and improves prognosis. However, blood pressure lowering effects were found to be similar among angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and calcium channel blockers.

• 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.

• A significant reduction in the incidence of heart failure was a common benefit observed in all the three trials.
• In the MICROHOPE study, a substudy with a different focus that did not involve primary blood pressure-lowering study, reported similar benefits with angiotensin converting enzyme inhibition in diabetic patients as observed in the HOPE trial. Similar prognosis was also observed in the high-risk and intermediate risk groups with the use of ramipril and perindopril respectively.

• In diabetics with post-MI, ACE inhibition may slow the rate of progression of proteinuric chronic renal failure.

Indications

• ACE inhibition has been shown to be effective in the treatment of stable angina only with co-existing hypertension, diabetes, heart failure, asymptomatic LV dysfunction, or post-MI. Efficacy has not been shown otherwise.

• In patients with coronary artery disease and preserved left ventricular function, ACEIs may be indicated for secondary preventive therapy.

• ACEIs or ARBs has shown to prevent the progression of renal dysfunction and hence are used as the first-line of agents in the management of hypertension in diabetics with microalbuminuria.

• ARBs may be used in patients who are intolerant to ACEIs and are indicated in stable angina patients with concomitant heart failure, hypertension or diabetic renal dysfunction. However, ARBs may not be indicated in patients with preserved LV function as a secondary preventive therapy.

Adverse Effects

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.

• Data collected from the PERSUADE substudy further strengthened the benefit of perindopril in the reduction of major cardiovascular events in diabetic patients with coronary disease.

• In another substudy, involving 12,056 patients with stable coronary artery disease without heart failure which assessed the benefit of ACE inhibition in patients with mild to moderate renal insufficiency, researchers reported similar benefits of perindopril consistent with the EUROPA trial. Researchers also stated that the effects of ACE inhibition were not modified by the presence of mild to moderate renal insufficiency.

• 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.

• In the VALIANT trial, 14,703 post-MI patients with heart failure, reported no significant difference in the prognosis of ischemic heart disease between the valsartan and captopril groups.

• 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 PEACE trial, 8,290 patients with a mean baseline blood pressure 133/78, were randomized to receive either trandolapril (4mg/day) or placebo. Researchers hypothesized that patients with stable coronary artery disease without heart failure derive therapeutic benefit from the addition of ACE inhibitors to conventional therapy. The primary end point from all causes of mortality, MI, coronary revascularization during a median 4.8 year follow-up did not differ between the two groups: 21.9% in the trandolapril group and 22.5% in the placebo group (p=0.43). Thus, the study concluded that the addition of an ACE inhibitor provided no further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization.

• In the TRACE study, a consequent to PEACE trial which involved 1,749 diabetic post-MI patients with LV dysfunction who were assessed for the efficacy of long-term treatment with the angiotensin-converting enzyme inhibitor, researchers reported a non-significant reduction in non-fatal MI observed at 26-month follow-up. However, trandolapril markedly reduced the risk of progression to severe heart failure.

• 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)

Class I

"1. ACE inhibitors should be started and continued indefinitely in all patients with left ventricular ejection fraction less than or equal to 40% and in those with hypertension, diabetes, or chronic kidney disease unless contraindicated. (Level of Evidence: A) "

"2. ACE inhibitors should be started and continued indefinitely in patients who are not lower risk (lower risk defined as those with normal left ventricular ejection fraction in whom cardiovascular risk factors are well controlled and revascularization has been performed), unless contraindicated. (Level of Evidence: B) "

"3. Angiotensin receptor blockers are recommended for patients who have hypertension, have indications for but are intolerant of ACE inhibitors, have heart failure, or have had a myocardial infarction with left ventricular ejection fraction less than or equal to 40%. (Level of Evidence: A) "

"4. Aldosterone blockade is recommended for use in post-MI patients without significant renal dysfunction (creatinine should be less than 2.5 mg per dL in men and less than 2.0 mg per dL in women) or hyperkalemia (potassium should be less than 5.0 mEq per L) who are already receiving therapeutic doses of an ACE inhibitor and a beta blocker, have a left ventricular ejection fraction less than or equal to 40%, and have either diabetes or heart failure. (Level of Evidence: A) "

"5. ACE inhibitor in patients with CAD* who also have diabetes and/or left ventricular systolic dysfunction. (Level of Evidence: A) "

“

* Significant CAD by angiography or previous MI.

”

Class IIa

"1. It is reasonable to use ACE inhibitors among lower-risk patients with mildly reduced or normal left ventricular ejection fraction in whom cardiovascular risk factors are well controlled and revascularization has been performed. (Level of Evidence: B) "

"2. ACE inhibitor in all patients with CAD* or other vascular disease.(Level of Evidence: B) "

“

* Significant CAD by angiography or previous MI.

”

Class IIb

"1. Angiotensin receptor blockers may be considered in combination with ACE inhibitors for heart failure due to left ventricular systolic dysfunction. (Level of Evidence: B) "

ESC Guidelines- Pharmacological Therapy to Improve Prognosis in Patients with Stable Angina (DO NOT EDIT)

Renin-Angiotensin-Aldosterone Receptor Blockers (DO NOT EDIT)

Class I

"1. ACE-inhibitor therapy in patients with coincident indications for ACE-inhibition, such as hypertension, heart failure, LV dysfunction, prior MI with LV dysfunction, or diabetes. (Level of Evidence: A) "

Class IIa

"1. ACE-inhibitor therapy in all patients with angina and proven coronary disease. (Level of Evidence: B) "