Part v

• Indications of RAS Blockade in CAD • Limitation and Adverse Reactions of ACE-I Therapy • Contraindications to ACE-I and ARB Therapy • Preparations and Dosage of ACE-I and ARBs INDICATIONS OF RAS BLOCKADE IN CAD
• Impaired LV systolic function. • Acute coronary syndromes. • Chronic stable angina in high risk patients. • Prevention of coronary events among high risk patients with atherosclerosis. • Prevention of coronary events in high risk-patients with diabetes. By high risk is meant: - more than two risk factors (old age, dyslipidemia, hypertension, smoking, family history) or poor LV systolic function (EF <40%). Use of ACE-Inhibitors in AMI (ACC/AHA recommendations-2004)

- Patients within the first 24 hours of a suspected acute MI with ST -segment elevation in two or more anterior precordial leads or with clinical heart failure in the absence of hypotension (systolic blood pressure < 100 mmHg) or known contraindications to ACE inhibitors. - Patients with MI and LV ejection fraction < 40% or patients with clinical heart failure on the basis of systolic pump dysfunction during and after convalescence from acute MI. - All other patients within the first 24 hours of a suspected or established acute MI, provided significant hypotension or other clear-cut contraindications are absent. - Asymptomatic patients with mildly impaired LV function (ejection fraction 40%-50%) and - Patients who have recently recovered from MI but have normal or mildly abnormal I: Universal agreement. IIa: majority favour this indication.

Acute Myocardial Infarction (AMI)
- All patients suffering from AMI should receive ACE-I therapy within 24 hours of presentation unless there is a contraindication (SBP< 90 mmHg, history of allergy to ACE-I, bilateral renal artery stenosis). - Any ACE-I can be used, the beneficial effect is a class effect for all ACE-I. - Elderly patients, patients with normal LV function and patients with elevated s. creatinine - The greatest benefit of ACE-I therapy is seen in patients with: § Frank heart failure or pulmonary oedema. § Tachycardia (heart rate > 100 beats/min at entery). Duration Of ACE-I Therapy Following AMI • Depends upon: - LV systolic function. • The following groups should receive ACE-I indefinitely; 1. Heart failure patients. 2. Asymptomatic LV systolic dysfunction. 3. High risk patients with atherosclerotic cardiovascular disease: abdominal aortic aneurysm, cerebrovascular disease, peripheral arterial disease. 4. Diabetic patients with additional cardiovascular risk factors (hypertension, dyslipidemia, The benefit of ACE-I is seen very early within few days after AMI. - ACE-I therapy may be discontinued in patients with small MI who have normal LV function and no other cardiovascular risk factors after an initial period of 6-8 weeks of ACE-I administration. Initiation and Monitoring of ACE-I Therapy
- Start soon after AMI at low doses orally with careful monitoring of blood pressure. - Although different ACE-I show differences in their affinity for the cardiac RAS, the protective effect post-MI appear to be a class effect. - Rapid upward titration of the dose (within 7 days) to reach the maximum dose may be useful provided BP and kidney function are carefully monitored. - In unstable patients with low blood pressure (SBP < 90-100 mmHg), captopril is the ACE-I of choice because of its short duration of action. 1. Captopril: initial dose 6.25mg, increased at 6-8 hours intervals to a maximum of 50 mg TID as long as SBP is above 90-100 mmHg. 2. Enalapril: initial dose 2.5 mg/day increased up to 20 mg BID. 3. Lisinopril: initial dose 2.5 mg/day increased to a maximum of 10-20 mg/day. 4. Ramipril: initial dose 2.5 mg/day increased to a maximum of 10 mg/ day. 5. Perindopril: initial dose 2 mg increased to a maximum of 8 mg/day.
- Role of ARBs
§ In patients with AMI who are intolerant to ACE-I (cough or allergic reaction), an ARB - Valsartan: initial dose 40 mg twice/day increased up to 160 mg twice/day. - Candesartan: initial dose 4 mg/day increased up to 16-32 mg/day. § ARB therapy should not be given in addition to an ACE-I in the immediate post-MI setting. This recommendation differs from that in patients with chronic heart failure,
Other Acute Coronary Syndromes- Unstable angina and NSTE MI
Whether ACE-I therapy should be initiated in patients with ACS other than AMI is not clear. - ACE-I (ramipril, perindopril) should be administered to high cardiovascular risk patients particularly those with diabetes, impaired LV function and multiple risk factors. - It is possible that ACE-I therapy as shown with ramipril (HOPE study) may prevent the development of MI, due to prevention of plaque rupture. Other Indications for ACE-I in Coronary Patients
First Priority - Chronic stable angina in a patient with diabetes, multiple cardiovascular risk factors or in presence of other atherosclerotic disease (e.g. peripheral, cerebral, aortic). - Any patient with CAD and impaired LV systolic function. - Patient with a history of MI who is diabetic or have multiple risk factors or have associated - ACE-I therapy (ramipril, perindopril) is recommended in all patients with CAD independent of LIMITATION AND ADVERSE REACTIONS OF ACE-I THERAPY
* Hypotension
- The major problem with ACE-I therapy in patients with CAD is inappropriate fall in blood pressure. The complication is more common in hypovolemic patients, the elderly or those on diuretic therapy. - Significant hypotension (SBP < 80 mmHg) can compromise coronary, renal and cerebral perfusion and lead to further deterioration in cardiovascular status particularly in patients with AMI. - When the risk of possible significant hypotension is suspected, it is recommended to start ACE-I therapy with captopril which is short acting drug and its adverse actions disappear rapidly. - Always start with a small dose and titrate the dose upward gradually to reach the maximal - Blood pressure should be monitored more frequently in the supine and standing positions particularly in the elderly, in patients receiving diuretics or nitrates, or patients with symptoms of unexpected weakness, dizziness or presyncope. * Renal Failure
- A rise in serum creatinine is expected during the first few weeks of ACE-I therapy in a good - ACE-I therapy should be discontinued if serum creatinine is suddenly increased beyond 25% of the initial level or if there is progressive increase of creatinine over repeated measurements at 5 to 7 days intervals. - ACE-I therapy can be restarted gradually at a small dose after return of serum creatinine level to baseline level and with adequate hydration and exclusion of bilateral renal artery stenosis. - Serum creatinine is monitored at weekly intervals during initiation of therapy in patients receiving diuretic therapy or with a history of renal trouble; otherwise, s. creatining is measured every 1-3 months.
* Hyperkalemia
- Incidence of 10-30%. - It is an uncommon complication of therapy with ACE-I or ARBs in patients without risk factors for - Patients at greatest risk of hyperkalemia: § Impaired renal function- chronic kideney disease- oliguria. § Decompensated congestive heart failure. § Drugs interfering with renal potassium excretion: o Potassium-sparing diuretics: spironolactone, eplerenone, amiloride, triametrene. o Beta blockers, heparin, ketoconazole, cyclosporine. § Initiate therapy with low-dose ACE-I or ARB. § Measure potassium 1 week after initiating therapy or after increasing dose of drug. § If potassium increases > 5.5 mmol/litre, decrease the dose of the drug. § Dose of spironolactone should not exceed 25 mg daily when used with ACE-I or ARB. Avoid this combination when the GFR is < 30 ml/min. § Discontinue spironolactone if potassium is > 5.5 mmol/litre. § Do not give potassium supplements or potassium rich foods (orange juice, melon and § If serum potassium concentration is more than 5.6 mmol/litre despite the previous precautions § Particular attention should be given to patients with cardiac conduction disturbances since mild degrees of hyperkalemia can precipitate heart block. § Monitoring of serum potassium is done at the same time of creatinine following the previous * Cough
- Dry irritant cough described sometimes as a tickling sensation in the throat is present in up to 30% of patients receiving ACE-I therapy. - Cough may be severe enough to interfere with patients sleep or quality of life and necessitates - ARB can be administered as an alternative to ACE-I.
* Allergic Reactions
- Skin rash, maculo papular is uncommon complication with the current dosage recommendation.
- Angioneurotic oedema is rare.
- Acute deterioration of kidney function was reported with very big dose of ACE-I secondary to
* Contraindications to ACE-I and ARB Therapy
2. Previous history of allergic reaction to ACE-I or ARB. 4. Renal artery stenosis in a single functioning kidney. Table (23-1): Preparations and Dosage of ACE-I and ARBs
Maintenance or Maximal
Drug Name
Trade Name
Initial Dose
1. Arnold JMO, Yusuf S, Young J. Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation.2003;107:1284-1290 2. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure- lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomized trials. Lancet.2003;362:1527-35 3. Cohn JN. Val-HeFT: changing the heart failure horizon. Euro Heart J Suppl.2003; (suppl C): 4. Fogari R, Zoppi A, Lazzari P, et al. ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance in overweight hypertensive patients. J Cardiovasc Pharmacol.1998;32(4):616-619 5. Givertz MM, Manipulation of the renin-angiotensin system. Circulation.2001;104: e14-e18 6. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet.1999;353:611-16 7. Kostis JB. The Effect of enalapril on mortal and morbid events in patients with hypertension and left ventricular dysfunction. AJH.1999;8:909-914 8. Levy BI. Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Circulation.2004;109:8-13 9. Lonn EM, Yusuf S, Dzavik V. Effects of ramipril and vitamin E on atherosclerosis. 10. Mann JEE. Gerstein HC, Yi Q, at al. Development of renal disease in people at high cardiovascular risk: results of the HOPE Randomized Study. J Am Soc Nephrol. 2003;14:641-647 11. Menard J, Azizi M. Renin-angiotensin system blockade: to what extent? J 12. Munzel T, Keaney JF. Are ACE Inhibitors a "Magic Bullet: against Oxidative Stress? 13. Nicholls MG, Roberston Jis. The renin-angiotensin system in the year 2000. J Hum Hypertens. 14. Niklason A, Hedner T, Niskanen L, et al. Development of diabetes is retarded by ACE inhibition in hypertensive patients – a subanalysis of the captopril prevention project (CAPPP). J Hypertens.2004;22:645-652 15. Niskanen L, Lanke J, Hedner T, et al. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/ B-blocker-based treatment regimen. Diabetes Care.2001;24:2091-2096 16. Otterstad J, Sleight P. The HOPE study: comparison with other trials of secondary prevention. 17. Pahor M, Franse LV, Deitcher SR. et al. Fosinopril versus amlodipine comparative treatments study. Circulation.2002;105:457-461 18. Pitt B. ACE inhibitors for patients with vascular disease without left ventricular dysfunction – May they rest in PEACE? N Engl J Med.2004. 351;20:2115-2117 19. Remme WJ. Reconsidering the management of all coronary artery disease patients: importance of the EUROPA trial. Euro Heart J Suppl.2003; 5 (suppl E): E23-E30 20. Schieffer B, Schieffer E, Hilfiker-Kleiner D, et al. Expression of angiotensin II and interleukin 6 in human coronary atherosclerotic plaques. Circulation.2000;101:1372-1378 21. Sleight P, Yusuf S. New evidence on the importance of the renin-angiotensin system in the treatment of higher-risk patients with hypertension. J Hypertens.2003;21:1599-1608 22. Tatti P, Guarisco R, Pahor M, et al. Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. 23. Teo KK, Burton JR, Buller CE, et al. Long-term effects of cholesterol lowering and angiotensin- converting enzyme inhibition on coronary atherosclerosis. Circulation.2000; 102: 1748-1754 24. The PEACE trial Investigators. Angiotensin-Converting-Enzyme inhibition in stable coronary artery disease. N Engl J Med.2004;351:2058-68 25. Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ.2001; 26. Zhou M, Adam A, Raij L. Interaction among angiotensin II, nitric oxide and oxidative stress.


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