|
|
| Line 20: |
Line 20: |
| {{Editor Help}} | | {{Editor Help}} |
|
| |
|
| '''Inhibition of the renin-angiotensin-aldosterone system''' is a key therapeutic maneuver in patients with STEMI.
| |
|
| |
|
| The best known regulator of blood pressure and determinant of target organ damage from hypertension is the renin-angiotensin-aldosterone system. Overexpression of [[renin]] and its metabolic products predisposes to increased blood pressure and even frank [[hypertension]], as well as target organ damage. [[Renin]] reacts with angiotensinogen to produce the decapeptide [[angiotensin I]], which is biologically inactive. [[Angiotensin I]] is cleaved by a variety of enzymes, including [[angiotensin converting enzyme]] (ACE) and other proteolytic enzymes, e.g. the serine protease chymase, to generate [[angiotensin II]], an octapeptide that is responsible for most of the known biological activity of the system. In addition, non-renin-enzymes, including tonin and cathepsin, are capable of generating [[angiotensin II]] directly from [[angiotensinogen]]. The angiotensin peptides, angiotensin I and II, are susceptible to digestion at a number of sites by angiotensinases. The resultant peptide fragments are found in the circulation and have functions that may be distinct from those of [[angiotensin II]]. For example, angiotensin III (the 2-8 peptide) has functions identical to those of [[angiotensin II]], while angiotensin IV (the 3-8 peptide) may bind selectively to a novel receptor (AT4) and stimulate release of [[plasminogen activator inhibitor-1]] (PA1-1), a potent anti-thrombolytic, and the (1-7) peptide may bind to the AT3 receptor to stimulate vasodilation and potentiate [[bradykinin]]. The biological significance of these novel peptides has yet to be fully elucidated.
| |
|
| |
| [[Angiotensin II]] elevates blood pressure by a variety of mechanisms, including direct vasoconstriction, potentiation of [[sympathetic nervous system]] activity at both central and peripheral levels, stimulation of [[aldosterone]] synthesis and release with consequent [[sodium]] and fluid retention by the kidney and stimulation of [[arginine vasopressin]] release. In addition, [[angiotensin II]] has a variety of actions that damage blood vessels directly. For example, it stimulates NADH and NADPH activity, raising the oxidative potential of vascular tissue. [[Angiotensin II]] also plays a role in the vascular injury response, stimulating leukocyte adhesion to the site of injury and favoring superoxide and peroxynitrite formation and proliferation and migration of various cell types toward the luminal site of injury. The events that follow cause cellular components of the arterial wall to transform their phenotypes, resulting in atherosclerotic plaque or fibrous neointima formation. [[Angiotensin II]] and some of its constituent peptides also stimulate synthesis of the antithrombolytic agent, PAI-1, suggesting that activation of the renin-angiotensin-aldosterone system predisposes to atherosclerosis and thromboembolic events, including [[acute myocardial infarction]] and [[stroke]].<ref name="pmid8104270">{{cite journal |author= |title=Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators |journal=Lancet |volume=342 |issue=8875 |pages=821–8 |year=1993 |month=October |pmid=8104270 |doi= |url=}}</ref><ref name="pmid7477219">{{cite journal |author=Køber L, Torp-Pedersen C, Carlsen JE, ''et al'' |title=A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group |journal=N. Engl. J. Med. |volume=333 |issue=25 |pages=1670–6 |year=1995 |month=December |pmid=7477219 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=7477219&promo=ONFLNS19}}</ref><ref name="pmid7661937">{{cite journal |author= |title=ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group |journal=Lancet |volume=345 |issue=8951 |pages=669–85 |year=1995 |month=March |pmid=7661937 |doi= |url=}}</ref><ref name="pmid7910229">{{cite journal |author= |title=GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico |journal=Lancet |volume=343 |issue=8906 |pages=1115–22 |year=1994 |month=May |pmid=7910229 |doi= |url=}}</ref><ref name="pmid1495520">{{cite journal |author=Swedberg K, Held P, Kjekshus J, Rasmussen K, Rydén L, Wedel H |title=Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) |journal=N. Engl. J. Med. |volume=327 |issue=10 |pages=678–84 |year=1992 |month=September |pmid=1495520 |doi= |url=}}</ref><ref name="pmid7923656">{{cite journal |author=Rutherford JD, Pfeffer MA, Moyé LA, ''et al'' |title=Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators |journal=Circulation |volume=90 |issue=4 |pages=1731–8 |year=1994 |month=October |pmid=7923656 |doi= |url=}}</ref><ref name="pmid9193433">{{cite journal |author=Pfeffer MA, Greaves SC, Arnold JM, ''et al'' |title=Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction. The healing and early afterload reducing therapy trial |journal=Circulation |volume=95 |issue=12 |pages=2643–51 |year=1997 |month=June |pmid=9193433 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=9193433}}</ref><ref name="pmid16755193">{{cite journal |author=Tokmakova M, Solomon SD |title=Inhibiting the renin-angiotensin system in myocardial infarction and heart failure: lessons from SAVE, VALIANT and CHARM, and other clinical trials |journal=Curr. Opin. Cardiol. |volume=21 |issue=4 |pages=268–72 |year=2006 |month=July |pmid=16755193 |doi=10.1097/01.hco.0000231394.79609.24 |url=}}</ref><ref name="pmid7586285">{{cite journal |author=Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G |title=ACE inhibitor use in patients with myocardial infarction. Summary of evidence from clinical trials |journal=Circulation |volume=92 |issue=10 |pages=3132–7 |year=1995 |month=November |pmid=7586285 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=7586285}}</ref><ref name="pmid7990904">{{cite journal |author=Ambrosioni E, Borghi C, Magnani B |title=The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators |journal=N. Engl. J. Med. |volume=332 |issue=2 |pages=80–5 |year=1995 |month=January |pmid=7990904 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=7990904&promo=ONFLNS19}}</ref><ref name="pmid7885123">{{cite journal |author= |title=Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1) |journal=Lancet |volume=345 |issue=8951 |pages=686–7 |year=1995 |month=March |pmid=7885123 |doi= |url=}}</ref><ref name="pmid9631869">{{cite journal |author= |title=Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group |journal=Circulation |volume=97 |issue=22 |pages=2202–12 |year=1998 |month=June |pmid=9631869 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=9631869}}</ref><ref name="pmid8076657">{{cite journal |author=Sigurdsson A, Swedberg K |title=Left ventricular remodelling, neurohormonal activation and early treatment with enalapril (CONSENSUS II) following myocardial infarction |journal=Eur. Heart J. |volume=15 Suppl B |issue= |pages=14–9; discussion 26–30 |year=1994 |month=May |pmid=8076657 |doi= |url=}}</ref>
| |
|
| |
| ==Mechanism of Benefit==
| |
|
| |
| Pharmacological agents that antagonize the renin-angiotensin-aldosterone system at the level of ACE, the angiotensin II receptor, and more recently, the aldosterone (mineralocorticoid) receptor, have come into prominence in the treatment of hypertension, heart failure and post-myocardial infarction cardiac remodeling. These agents are highly effective in lowering blood pressure and, particularly in the case of the angiotensin II receptor antagonists, are extremely well tolerated.<ref name="pmid8104270">{{cite journal |author= |title=Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators |journal=Lancet |volume=342 |issue=8875 |pages=821–8 |year=1993 |month=October |pmid=8104270 |doi= |url=}}</ref><ref name="pmid7477219">{{cite journal |author=Køber L, Torp-Pedersen C, Carlsen JE, ''et al'' |title=A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group |journal=N. Engl. J. Med. |volume=333 |issue=25 |pages=1670–6 |year=1995 |month=December |pmid=7477219 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=7477219&promo=ONFLNS19}}</ref><ref name="pmid7661937">{{cite journal |author= |title=ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group |journal=Lancet |volume=345 |issue=8951 |pages=669–85 |year=1995 |month=March |pmid=7661937 |doi= |url=}}</ref><ref name="pmid7910229">{{cite journal |author= |title=GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico |journal=Lancet |volume=343 |issue=8906 |pages=1115–22 |year=1994 |month=May |pmid=7910229 |doi= |url=}}</ref><ref name="pmid1495520">{{cite journal |author=Swedberg K, Held P, Kjekshus J, Rasmussen K, Rydén L, Wedel H |title=Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) |journal=N. Engl. J. Med. |volume=327 |issue=10 |pages=678–84 |year=1992 |month=September |pmid=1495520 |doi= |url=}}</ref><ref name="pmid9631866">{{cite journal |author=Pfeffer MA |title=ACE inhibitors in acute myocardial infarction: patient selection and timing |journal=Circulation |volume=97 |issue=22 |pages=2192–4 |year=1998 |month=June |pmid=9631866 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=9631866}}</ref><ref name="pmid7923656">{{cite journal |author=Rutherford JD, Pfeffer MA, Moyé LA, ''et al'' |title=Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial. SAVE Investigators |journal=Circulation |volume=90 |issue=4 |pages=1731–8 |year=1994 |month=October |pmid=7923656 |doi= |url=}}</ref><ref name="pmid14610160">{{cite journal |author=Pfeffer MA, McMurray JJ, Velazquez EJ, ''et al'' |title=Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both |journal=N. Engl. J. Med. |volume=349 |issue=20 |pages=1893–906 |year=2003 |month=November |pmid=14610160 |doi=10.1056/NEJMoa032292 |url=}}</ref><ref name="pmid12668699">{{cite journal |author=Pitt B, Remme W, Zannad F, ''et al'' |title=Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction |journal=N. Engl. J. Med. |volume=348 |issue=14 |pages=1309–21 |year=2003 |month=April |pmid=12668699 |doi=10.1056/NEJMoa030207 |url=}}</ref><ref name="pmid9193433">{{cite journal |author=Pfeffer MA, Greaves SC, Arnold JM, ''et al'' |title=Early versus delayed angiotensin-converting enzyme inhibition therapy in acute myocardial infarction. The healing and early afterload reducing therapy trial |journal=Circulation |volume=95 |issue=12 |pages=2643–51 |year=1997 |month=June |pmid=9193433 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=9193433}}</ref><ref name="pmid16755193">{{cite journal |author=Tokmakova M, Solomon SD |title=Inhibiting the renin-angiotensin system in myocardial infarction and heart failure: lessons from SAVE, VALIANT and CHARM, and other clinical trials |journal=Curr. Opin. Cardiol. |volume=21 |issue=4 |pages=268–72 |year=2006 |month=July |pmid=16755193 |doi=10.1097/01.hco.0000231394.79609.24 |url=}}</ref><ref name="pmid14557343">{{cite journal |author=Pitt B |title=Aldosterone blockade in patients with systolic left ventricular dysfunction |journal=Circulation |volume=108 |issue=15 |pages=1790–4 |year=2003 |month=October |pmid=14557343 |doi=10.1161/01.CIR.0000086776.15268.22 |url=}}</ref><ref name="pmid7586285">{{cite journal |author=Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G |title=ACE inhibitor use in patients with myocardial infarction. Summary of evidence from clinical trials |journal=Circulation |volume=92 |issue=10 |pages=3132–7 |year=1995 |month=November |pmid=7586285 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=7586285}}</ref><ref name="pmid7990904">{{cite journal |author=Ambrosioni E, Borghi C, Magnani B |title=The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators |journal=N. Engl. J. Med. |volume=332 |issue=2 |pages=80–5 |year=1995 |month=January |pmid=7990904 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=7990904&promo=ONFLNS19}}</ref><ref> Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345</ref><ref name="pmid7885123">{{cite journal |author= |title=Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1) |journal=Lancet |volume=345 |issue=8951 |pages=686–7 |year=1995 |month=March |pmid=7885123 |doi= |url=}}</ref><ref name="pmid9631869">{{cite journal |author= |title=Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group |journal=Circulation |volume=97 |issue=22 |pages=2202–12 |year=1998 |month=June |pmid=9631869 |doi= |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=9631869}}</ref><ref name="pmid12383982">{{cite journal |author=Teo KK, Yusuf S, Pfeffer M, ''et al'' |title=Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: a systematic review |journal=Lancet |volume=360 |issue=9339 |pages=1037–43 |year=2002 |month=October |pmid=12383982 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S014067360211138X}}</ref><ref name="pmid11214765">{{cite journal |author=Meune C, Mahe I, Mourad JJ, ''et al'' |title=Interaction between angiotensin-converting enzyme inhibitors and aspirin: a review |journal=Eur. J. Clin. Pharmacol. |volume=56 |issue=9-10 |pages=609–20 |year=2000 |month=December |pmid=11214765 |doi= |url=}}</ref><ref name="pmid8076657">{{cite journal |author=Sigurdsson A, Swedberg K |title=Left ventricular remodelling, neurohormonal activation and early treatment with enalapril (CONSENSUS II) following myocardial infarction |journal=Eur. Heart J. |volume=15 Suppl B |issue= |pages=14–9; discussion 26–30 |year=1994 |month=May |pmid=8076657 |doi= |url=}}</ref>
| |
|
| |
| The major questions asked regarding the clinical utilization of the angiotensin receptor antagonists and the [[ACE inhibitor]]s are:
| |
|
| |
| * Do they have clinical benefits beyond blood pressure lowering?
| |
|
| |
| * Are their advantages sufficient to justify their high cost?
| |
|
| |
| * Is one class superior to the other with respect to preventing target organ damage and cardiovascular events?
| |
|
| |
| * Are the therapeutic effects of the two classes additive or synergistic?
| |
|
| |
| Clinical trial evidence to date is inconclusive on these points.
| |
|
| |
| ==Clinical Trial Data==
| |
|
| |
| Additional long-term controlled clinical trials are needed to clarify the benefits and risks of cardiovascular outcomes associated with blood pressure reduction induced by antihypertensive agents that antagonize components of the renin-angiotensin-aldosterone system in patients with multiple cardiovascular risk factors. The NHLBI-sponsored Antihypertensive and Lipid Lowering to Prevent Heart Attack (ALLHAT) trial is the largest of these trials, including over 42,000 high-risk hypertensive subjects with diverse ethnic backgrounds. ALLHAT is comparing ACE inhibitor or calcium channel blocker therapy to a diuretic based regimen with respect to prevention of major cardiovascular disease outcomes. This massive trial should provide important answers to many of these pressing questions. For the rest, we need more fundamental information about the biology of the renin-angiotensin-aldosterone system in human subjects.
| |
|
| |
| ==Dosing==
| |
|
| |
| ==Side Effects==
| |
|
| |
| ==Guidelines==
| |
|
| |
| ===[[Guidelines for ACE Inhibitors Therapy]] <ref name="Antman"> Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ, Pearle DL, Sloan MA, Smith SC Jr; 2004 Writing Committee Members, Anbe DT, Kushner FG, Ornato JP, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. '' Circulation 2008 Jan 15;117(2):296-329 PMID 18071078</ref> </small>===
| |
|
| |
| ===[[Guidelines for Angiotensin Receptor Blockers Therapy]] <ref name="Antman"> Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ, Pearle DL, Sloan MA, Smith SC Jr; 2004 Writing Committee Members, Anbe DT, Kushner FG, Ornato JP, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. '' Circulation 2008 Jan 15;117(2):296-329 PMID 18071078</ref> </small>===
| |
|
| |
| ===[[Guidelines for Aldosterone Blockers Therapy]] <ref name="Antman"> Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ, Pearle DL, Sloan MA, Smith SC Jr; 2004 Writing Committee Members, Anbe DT, Kushner FG, Ornato JP, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. '' Circulation 2008 Jan 15;117(2):296-329 PMID 18071078</ref> </small>===
| |
|
| |
| ===[[Guidelines for Inhibition of the Renin-Angiotensin-Aldosterone System]] <ref name="Antman"> Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, Hochman JS, Krumholz HM, Lamas GA, Mullany CJ, Pearle DL, Sloan MA, Smith SC Jr; 2004 Writing Committee Members, Anbe DT, Kushner FG, Ornato JP, Jacobs AK, Adams CD, Anderson JL, Buller CE, Creager MA, Ettinger SM, Halperin JL, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B, Tarkington LG, Yancy CW. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. '' Circulation 2008 Jan 15;117(2):296-329 PMID 18071078</ref> </small> ===
| |
|
| |
|
| ==Guidelines (Do not edit)== | | ==Guidelines (Do not edit)== |
