eNAME=SAMRA SOOMRO eTOPIC=ACE INHIBITORS e UNIVERSITY=LIAQUAT UNIVERSITY OF MEDICAL AND HEALTH SCIENCES JAMSHORO eDEPARTMENT=PHARM-D eYEAR= FINAL YEAR OF PHARMACY oEMAIL= samrasoomro615@gmail.c omList of articles with author name and references Ee MioiAe 1 ALDEN, MD \WHLLIAM 8 APPLEGATE, Mo, MPH £580. WILLIAMSON, no, MHS CURT 9 FURBERG, MD. PH References ‘Ginical Care/Education/Nutrition shal paps 0, Mo. victor ey, MO, ts mo, Moche Share, MD. Zhan Axed MD. MD, snl Joshua We Reference American lournal of Kidney Diseases, Vol 40, No S (November), 2002: pp 1073-1029 aioe, Alberto Gale Navaro-Cd cents Labera Lue Ml Reference htto://dx doi org/10_1080/08037050213760 fdmond €xUt alas Heranz James M Wright? 4 and Medial Program, Unersty of Brien Columbia, Vitoria, Conads. 20epartment of Anesthesia Pharmacology and Therapeutes, Uniertty of Betish Columbia, Vancower, Canad Reference shecochranelibrary com | Pawek nD. uth A, Dudley, 8 Shannon Or, 8S Pavel S. Gideon, .N. Kath Hal, 8S, and Wayne A Roy, PD. Reference ‘gpg med 354.73 www neimorg ne 8, 2006SUMMARY ACE inhibitors (angiotensin converting enzyme) are one class of antihypertensive agent. They are recommended as a first line treatment of hypertension in patients with a variety of compelling indication inducing high coronary disease risk or history of diabetes, stroke , heart failure, myocardial infarction or chronic kidney disease. These drug block the enzyme ACE which cleavage angiotensin | to form a potent vasoconstrictor angiotensin II.ACE is also responsible for breakdown of bradykinin, a peptide that increase the production of nitric oxide and prostacyclin by the blood vessels. Both nitric oxide and prostacyclin are potent vasodilator. Ace inhibitors decrease angiotensin ll and increase bradykinin level. By reducing angiotensin II level, Ace inhibitors also decrease the secretion of aldosterone, resulting in decrease sodium and water retention « Therapeutic benefit of ace inhibitors as compared with other antihypertensive agent in patient with type II diabetes: Recent comparative trails and observational studies in diabetes have suggested that for the prevention of the cardiovascular events ace inhibitors may be superior to alternativeantihypertensive agents. That, the greater benefits of ace inhibitors was explained by better blood pressure controls indicates that other mechanism related to ace inhibitors may have played an additional role in preventation of major clinical events. The available data supports the view that compared with alternative agents tested, ace inhibitors appeared to provide a special advantage on addition to blood pressure control. Based on available data from comparative trails, using ace inhibitors may be prudent as a first line agents for treatment of hypertension in patient with type I diabetes ACE inhibitor versus ARB’S for primary hypertension: angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are widely prescribed for primary hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg). However, while ACE inhibitors have been shown to reduce mortality and morbidity in placebo-controlled trials, ARBs have not. Therefore, a comparison of the efficacies of these two drug classes in primary hypertension for preventing total mortality and cardiovascularevents is important. We found no reliable difference between ACE inhibitors and ARBs for total deaths, deaths due to heart disease, or total heart disease and stroke. However, our conclusions alone cannot be taken to mean that ARBs would show similar benefit like ACE inhibitors if compared with placebo (a dummy treatment). ARBs do have a 1.8% lower chance of being stopped due to side effects over 4.1 years, meaning that for every 55 people treated with an ARB instead of an ACE inhibitor for 4.1 years, one person would be spared from a side effect leading to stopping the drug. This difference in side effects was mainly due to a higher rate of dry cough in people taking ACE inhibitors. ACE inhibitors and N-acetyl cysteine: SH group donors, such as thiosalicylic acid or N- acetyl cysteine (NAC), have been demonstrated to potentiate the hypotensive effect of acetylcholine, through an NO-dependent mechanism. There is some evidence that NO participates in the antihypertensive effect of the angiotensin converting enzyme inhibitors (ACEls). Therefore, since the hypotensive action of ACEls seems to be at least partially mediated by NO, SH group donors may enhance the antihypertensive effect of thesedrugs. Moreover, NAC potentiates the nitroglycerin hypotensive effect by NO- dependent mechanisms .NAC also increases the acetylcholine vasodilatory effect in spontaneously hypertensive as well as in normotensive rats [7]. Therefore, it is suggestive that NAC may enhance the vasodilatory effect of several substances through an NO-dependent mechanism. Therapeutic benefits of ACE inhibitors on haemodialysis patient: A study was conducted on effect on mortality in patients undergoing long-term haemodialysis therapy. Clinical data for patients on haemodialysis therapy between 1994 and 2000 were reviewed. Patients were grouped according to whether they had been treated with ACE inhibitors. Sixty patients had been treated with ACE inhibitors (treated group) and 66 patients had not (untreated group). Blood pressure reduction was not significantly different between the treated and untreated groups. Nevertheless, comparing the treated group with the untreated group, mortality was decreased significantly in the treated group, with a risk reduction of 52%.In treated patients 65years or younger, the absolute risk reduction of mortality was 79%. Although further research is needed, these preliminary findings suggest that ACE inhibitors, independently of their antihypertensive effect, may dramatically reduce mortality among chronic haemodialysis patients 65 years or younger. ACE inhibitors, independently of their effect on blood pressure, reduced mortal- ity in patients on chronic haemodialysis therapy. The present study has several limitations: the patient population is relatively small, and its design is retro prospective; therefore, patients were not randomized, and there was no standardization in the treatment protocol. Major Congenital Malformations after First- Trimester Exposure to ACE Inhibitors: Infants with only first-trimester exposure to ACE inhibitors had an increased risk of major congenital malformations as compared with infants who had no exposure to antihypertensive medications. In contrast, fetal exposure to other antihypertensive medications during only the first trimester did not confer an increased risk.Infants exposed to ACE inhibitors were at increased risk for malformations of the cardiovascular and the central nervous system.Exposure to ACE inhibitorsduring the first trimester cannot be considered safe and should be avoided.Clinical Care/Education/Nutrition Therapeut and Other Antihy ic Benefits of ACE Inhibitors pertensive Drugs Patients With Type 2 Diabetes ‘Manco Pauor, mp Bevce M, Psary, mp, ren Micuant H. ALDEN, seo Wau B. Arruncare, a, a Jerr D. Wintiaseson, seo, as ‘Curr D. Furs, Mp, ri (OBJECTIVE — To assess whether ACE inhibitors are superior to alternative agents for the [Prevention of cardiovascular events in patients with hypertension and type 2 diabetes. RESEARCH DESIGN AND METHODS — This study fs. areview and of ‘randomized controlled tials that included patients with type 2 diabetes and abo. ‘were randomized toan ACE inhibitor or an altemative drug, were followed for =2 years, and. brad adjudicated cardiovascular events. RESULTS — A otal of trials wove eligible. The Blood Pressure Coetrol in Dia- bates (ABCD) tial (a= 470) compared enalapril the Captopril Prevention. Project (CAPPP) (a 572) compared eapopel with diuretics o blockers. the Fosinopril Ver as Amlodipine Cardiovascular Events Til (FACET) (n = 380) foninopetl with: Stnlodipine’ andthe UK. Prospective Dabels Study (UKPDS) a = 758) compared taptoprl ‘vith atenolol. The cumulative results ofthe fist tals showed a benefit af ACE {inhibitors compared with alternative treatments on the outcomes of acute myocardial infare tion (63% reduction. P < 0.001), cardiovascular events (51% reduction, P< 0,001), and alll ‘ase mortality (62% reduction, P= 0.010). These findings were not observed in the UKPDS, ‘The ACK inti di not appear to be superior to other agents forthe outeore of stoke i any ofthe tia. None ofthe bindings were explained by in blood pressure contol CONCLUSIONS — sith the alternative agents bested, ACE inhibitors may pro- Sat pec cestage Nodton lod pranme one The quinoa Is oquivalent to eaploprl remains open. Conclusive evidence oa the comparative effets of ant Ihyperiensive treatments will come from large prospective randomize trials. Diabetes Care 23:488-892, 2000 treatment ts to prevent clinical com plications and not simply to lower ee- ‘vated blood pressure. Evidence from the ‘Systolic Hypertension in the Elderly Pro Ti primary goal of antihypertensive . ‘Foam the Sich Center on Aging (MP. WBA... ‘gram and the Systolic Hypertension in ‘Thal showed that. compared with. pheebo, treatment of hypertension in inacal onion (12) Dats om the Departures of Kerra MBean the Depa ‘at of Public Health Scencas(C DE}, Wake Favest Univers, Weston Salem. Neth Cara th Car ‘oeaseuar Health Research Unit MP), Departments ef Medicine, Epidemics and Heal Services Uniserty of Washington, Seat, Wasungon, and the Deparment of Epidemoogy aa Social Meine ALHLA)” Albert Einstein College of Medicine, Brom Neve fork ‘Adres convespondknce and ‘Salem NC 27157: Emull mpahor@whubme edt eee Te ra Nm Sah Coo ig ig seaman ns roi tae eae eee a ‘ceil at pleat Octet 1000 a accepted tn rex form 1 Rebruaty 2000 ‘Abbreviations: ABCD, Appropa ject, PACER Foinopil Vers Bvahuaton, ER relat rk: U acuta Everts Tia HOPE. Heart Ouacanes Preeti DS, UK. Prapactive Diabetes Stay An Dauber, CAPE Capp reversion Pro ‘Aableehewhace i this bbe shows conventunul and Syetmne luereutional (1 unt and conversion {ton for may siete Hypertension ‘Treatment trial and the U.K. Prospective Diabetes Study (UKPDS) suggest that. in patients with dia- betes. greater blood pressure reduction. results in greater clinical benefits (3.4) ‘Aithough these studies document that teat- iment of high blood pressure is beneficial is hypertensive patients with type 2 diabetes, none of these trials information oF the relative therapeutic benefit of indivical antihypertensive agents. Recent comparative trials and observa. tional studies in diabetes have suggested that, for the prevention of cardiovascular events, ACE Inhibitors may be superior to alternative antihypertensive agents (5,6) “That the greater benefit of ACE inhibitors ‘was not explained by better blood pressure ‘control indicates that other mechanisms Inked to ACE inhibition may have played an additional roe in the prevention of major lineal events. The purpase of the present review and meta-analysis ts to summarize the current evidence from randomized clin- {cal trials with clinical outcomes that ddrectly compared ACE inhibitors to alter- motive antihypertensive agents in patients ‘with hypertension and type 2 diabetes. RESEARCH DESIGN AND IMETHODS — Tp be included in the meta-analysis, a study had tobe a random, ized controlled trial published in a peer: reviewed journal that included patients ‘with type 2 diabetes and hypertension, ‘evaluated an ACE inhibitor versus an active ‘treatment, followed the participants for =2 smentochew fe acomnecestandicrst number of clinical events, and used prede fined criteria to adjudicate the cardiovas ‘cular events. Studies were identified through PubMed searches using the fol lowing key wards: “ACE inhibitors,” “di betes “hypertension.” and “clinial tial” The searches were extended through Jan ary 2000, Letters to the editor, commen. taries, review articles, editorials, and abservational studles were not Included. Bibliographies of te retrieve articles were searched to identify ather eligible studies, and information from colleagues was used te identity more recently published artiches, Dorris Can, vou 2 Nona 7 Tony 2000‘Table 1 Baseline characteristics according to teeatment Ag Men BMI Macesibuminaria Duration Systoicblood asta blood Thal Agent (as) 0) yn 106)_—_dabetes (ean) _presure (rm) pressure (rang) ABCD Empl 235577484 67 319259 19 A5268 156217 ‘i827 Nuoltipine 285 572282 68 313250 is 7268 155219 627 CAPER @) Captopril, = 300 550276 G3 309 164s 19 ors 10 DiuntiyP-blockes 263 587274 6) 303 183 +21 or 10 FACET ©) Fosinoped 180 628270 GL 907240 0 7291 17016 95 10 Anledipine 191 6.3461 58 B055A 0 0586 17 IB OB UKPDS(10)——“Captoped 400563381 51 208=58 2 26 150 220 ots 10 Nenobl 358 SA0282 57207253 3 27 150.2 19 8s 10 ‘Dee means» SEM, unk there iecate ‘The following elements were abstracted: design, sample size, randomized tteat- ‘ments, follow-up time, average age, sox dlstritution, average BM proportion of ctpants with macroalburinuria, dra enol dabtes selne astele ands tolic arterial pressures. and the number of events (including acute myocardial infare tion, stroke, combined cardiovascular events, and all-eause mortality) occurring {in each treatment group. “The Atial search identified 195 arti- cles. Of these trials met all the inckusion criteria Those trials were the ‘Blood Pressure Control in Diabetes (ABCD) trial (7), the diabetic group of the Captopeil Prevention Project (CAPPP) (8). the Fosino- pril Versus Amlodipine Cardiovascular Events Trial (FACET) (9), and the UKBDS able 1) (10). The recently published Swedish Thal in Old Patients with Hyper: tension-2 compared the use of B-blockers or diuretics with the use of ACE inhibitors or Ca” antagonists and was not included because outcome data in the subgroup of patients with diabetes in that study were not published and were not available from the authors (8. Dalhof, personal communication) (11) For the combined outcome of cardio vascular events, we adopted the definition used in each trial. In the ABCD trial, the cardiovascular events included cardiovas cular death, fatal and nonfatal acute ‘myacardial infarction, congestive heart fll ure requiring hospitalization, fatal or non- fatal stroke, and pulmonary infaretion, Because the number of events in patients with diabetes was not reported in the CAPE. we estimated these: numbers. by using the sample size, the relative risk (RE) (95% CD, and the P value ofthe difference hetween the 2 treatment groups. in the CCAPPP the cardiovascular events included cardiovascilar deaths, fatal and nonfatal acute myocardial infarction, and fatal. or nonfatal stroke. In the FACET, the cardlo~ ‘vascular events included fatal and nonfatal acute myocardial infarction, fatal and non- fatal stroke, and angina requiring baspital- tration. In the UKPDS, the cambined end point of cardiovascular events was not Teported. We calculated the total number of cardiovascular events by adding the num- ber of fatal and nonfatal acute myocardial infarctions and strokes, the number of con {gestive heart failure events. and the number of sudden deaths. Because more than 1 ‘event may have occurred ina singe patient. ‘this method is likely to have slightly over- ‘estimated the number of patients with car- diovascular events in the UKPDS. The overall relative risk (85% C1) of ach outcome was calculated with Petos method (12). Cochran tes fr heterogene- ity was used to assess the extent to which the differences among the tial results were because af random ns (13) RESULTS — Inthe 4 eligible trials (the ‘ABCD trial, the CAPPE. the FACET, and the UKPDS). the total number of partii- ts Was 2,180 (1.133 randomized to an “E inhibitor and 1,047 randomized to an alternative active agent) with a total fol low-up experience of 13,300 person- years. The participants’ characteristics ‘according to treatment are shown in Table 1. In the ABCD trial, the medication da dase was: 10-60 mg for 5-40 mg for enalapril In the CAPPE. 50 ‘mg captopril was given once or twice a day, and 50-100 mg atenolol or metopro- lol, 25 mg hydrochlorothiazide, ot 2.5 mg bendrofluazide was given once a day In the FACET, 20 mg fosinopril or 10 mg, amlodipine was given once a day In the UKPDS. the dose of captopril was 25-50 1g twice a day. and the dose of atenolol ‘was 50-100 mg once a daye In the ABCD trial the FACET, and the UKPDS, systolic (Fig. 1) and diastolic ‘blood pressure decreased signify with Hes teat el a ‘UKPDS, no significant eifferenceéver@ evi cent in blood pressure conivol among the randomized treatment groups. In the FACET, the patients randomized to amlodipine achieved a significantly lower Scie bid prea ea han fates randomized ta fosinopeil. Data on blood [pressure control in the diabetic patients of the CAPPP have not been reported. ‘The number of events by treatment pin each trial is shown in Table 2, and relative risks (95% Cl) of outcomes for ACE inhibitors versus other agents are epicted in Fig. 2. In the ACE inhibitor sgyoup, the risk of acute myocardial infarc: tion was significantly deereased in the ‘ABCD trial and the CAPPP. was nonsignif- ‘cantly lower in the FACET, and was non- significantly higher in the UKPDS compared with the alternative treatment. For the outcome of stroke, no significant clfferences were evident among treatments {in any of the trials In the ACE inhibitor sgyoup, the risk of combined cardiovascular events was significantly decreased in the [ABCD trial, the CAPPP and the FACET, and was cantly increased in the UKPDS compared with the alternative treatment; the risk of all-cause ‘was significantly decreased in the Ci was no lower in the ABCD trial and the FACET, and was nonsignifi- canily higher in the UKPDS. In initial analyses, the data ofthe 4 t- als were combined. For ACE inhibitors ver sus other treatments, the RRs (95% Cls} of acute myocardial infarction. stroke, cardio- vascular events, and all-cause mortality Disers Came vou 22 were 7 Toor 2000> Fosinopril + © Amlodipine 160 is t UKPDS... prenoiot 140 Enalapril ABCD ++ Nisoldipine 120 01234567869 Follow-up year BO ECeT ate URPUS The dns be CADP howl ben ered RD were 0.73 (0.54-0.90), 0.86 (0.59-1.26), dataset. No such diferences were evident 0.77 (0.61-0.91), and 0.85 (0.64-1.12), for the outcome of stroke. respecti potential outliers, we tested the heterogenelty af the results of CONCLUSIONS — ‘This review identi tals for cof inter- fled 4 trials in which patients with est cardiovascular events when the data of the [UKPDS were combined with the other 3 Irlals (P < 0.001 for both outcomes) but not when the UKPDS was excluded from the meu. ‘Thus, anly the data for the ABCD tral, the CAPPP and the FACET ‘were used in the formal meta-analytiecal- culations. When the data of the ABCD trial, ‘the CAPPE and the FACET were com ‘bined, the patients to an ACE ‘nhubitor had a significantly lower risk of ‘cule myocardial infarction, cardiovascular events, cad all-cause martality than these fandom to an alternative treatment Fig, _ geneity was found with the reduced diabetes and hypertension were teed to ether an ACE Inhibitor or to an alternative antihypertensive treatment and were followed for 2 years. The results of reviewed (0.001), aed all-cause mortality (62% neduc- tion, P = 0,010). These findings were not ‘observed in the UKPDS, which sak anil Tai to other agents eae in any of the tals. ‘ible 2— Number of clinical events according to inatment ‘Why do the results of the UKPDS differ from those the other tals? One possible compared sith te ober ses (ble). The re tion of follow-up in the UKPDS is another diference ffom the other trials. Another dernard eaten (10) aa they received an ACE inhibitor they occa uch os aur oe ventricular The net effect of such aselective dropout would be to dimin- ‘ah any differences between atenolol and Captopril, The potential frequent crossover between renders many aspects. of the UKPDS dificult to interpet (4. Another selective with an confirm the by a of ere sk evs he CAP by wig diuretics and individual 6 blockers. ‘fac band ne CNP ‘with the other 3 tials indicate that the ‘overall evidence of the comparative eflects of [ACE inhibitors is not yet conchasiv. FACE inhibitors are truly more bene {ictal than other agents far the treatment of hypertension in patients with diabetes, then what are the potential mechanisms? Blood pressure control did significantly between. treatme ABCD trial. In the FACET, the the ABCD trial and the FACET. Microal: Mean follow-up ACE inhibitors Other teapes Tal (Gear Agate AM Stoke CV Death gee a __AMI Stoke CV Death aco) = Ss Emalprh 23557 Stolp “aos nN 8 oT CAPPP() = G.1——Captopell 308102 30D ocker 2832520 ABET FACET @ 28 Feninopril «189-104 4A m1 om OS UKPDS (10)_84__G ete ental sas Daas a AMI, soe mpecanial aren: CV cardiac vert ooo ii Cie rcs 2 tne Te BO‘Acute myocardial infarction Cardiovascular events ‘Tial__na.9 cH PR tok aco .10g0r44) 4} wgem) | cape (17.67), | ———+-— (38.31) aoe FACET rust 75) +e, |= (Yer 08 120,821.75) tH zsyanaay ‘co, 2800.) ar ae.sn) a 4636-61) Facet mt ‘Stroke Allcause mortality paco saczeney = 41 mae) —+4 canme 1025.08) S— tian = racer s9( 124.28) (22300) eos 1121992121 ate, aco Gaope) ro1e1.22) 57 (36.47) FACET tw inones 1 2 ta omones 1 aR BOK! Anos ct 2 (95% CI) of cutcomes for ACE inhibitors compared with other agents inthe ABCD trial, the CAPPP the FACET, the UKPDS, andl in cunsned analyses. burminutia and serum creatinine levels during follow-up were similar in both treatment groups in the FACET. Metabolic control Is another Anportant factor that may aflectcarclo ‘outcomes. Inthe ABCD trial, the participants had poor metabolic control at baseline and during the 5 years af follow-up. but metabolic control was not significantly different between the ACE inhibitor and the Ca” antagonist-treated group. In the FACET, the patients randomized to the ACE Inhibwor or the Ca* antagontst achieved similar HbA,. and fasting glucose levels during follow-up. Changes in blood pres- -sure, metabolic cantrol, or othe risk fe tors during follow-up: were not reported for diabetic patents enralled in the CAPE ‘Thus, fromthe published data, differences In blood pressure contol, metabolic con: tool, or other measured risk factors likely explain the substantial difference tn major catdlovascular evens, Several other mechanisms not mea -sured tn the reviewed trials may account for a greater therapeutic benefit of ACE Inhibitors. ACE inhibitors may reduce ca diovascular tsk by improving endothelial dysfunction (16), by reducing inflamma tion (17), and by promoting fibrinolysis Inhibition af plastlnogens activa tor inhibitor 1 (18,19), The recently: pu lished Heart Outcomes Prevention Evaluation (HOPE) tial showed that the reduction In cardiovascular events with an ACE inhibitor was much greater than that expected ftom blood pressure reduction alone compared with placebo, which sup: ports the view that additional mechanisens Contribute to the prevention of eardiovas- cular events with ACE inhibition (20). The matn findings ofthe HOPE trial were con firmed, im patients with and without dla- betes. The HOPE trial was not included in the present meta-analysts because the com parlson group was treated with a placebo and not with an ative agent as required by the inclusion criteria. In summary. blood pressure reduc- lion per seis necessary to prevent clinical complications in bypertensive patients (21), but additional clinical benefits can be achieved by non-blood pressure mech- anisms. The evidence from the present review and meta-analysis of comparative trials in patients with hypertension and diabetes should not be considered ean- lusive. The available data support the view that, id with the alternative agents tested, ACE inhibitors appear ta prove spec avanag in atin to lood pressure control. The question of ‘whether atenolol is equlvalent to remain ope Bese on avalable daa from comparative trials, using ACE Inhibitors may be prudent as a first-line agent forthe treatment of hypertension in patlents with type 2 diabetes. Conclusive evidence on the comparative effects of antihypertensive treatments will come from large prospective randomized trials such as the Antihypertensive and Lipid Lowering ‘Treatment To Prevent Heart ‘Attack Trak (22) Pabor and Associates ;— The results ofthas sexy ‘were presented atthe 89th Annual Meeting of the American Diabetes Association, San Diego, CA, 19 June 1999, — SRE ay pee nana bee te es sees men nace pee Cha reac taeeia eee eran aoe ae Soa eee eee ele So eee eee Bee pn areas ae Pree Gp aaa Rare Ree 0, Bete WO ema tne ieetacrane mmo Seca Scouse ae eta te eeu re Heart pasen tea ttoenes et Uaenoeeees peo eaten ee lenient irene eee fey olny are ee cere ae 4. ‘Tit blood preaune cone and rl of lesan al aicoentie Ca Cations in type 2 diets UKPDS 38. 317-703-715. 1998 5, Palor M, Paty BM, Furberg CD: Theat iment of ive ‘with cla As Langlsoteno-d0 Tone 6, abr M. Peat BM, Furberg CD: New et- cence on the prevention of cardioverter evens in ties wih ype 2 Sines Cas Pama Sup Sie-s25, 1906 7, Bstaci RO,Jefers BW Hit WR, Big SL, Gilford N, Scher RW: The effect of tsa Capine as compared with eraapl on ex. Glovascular events In patients with pe diate ned hyper terion, N Engl Med 338 645-032, 1998 8, Hanston Lindholm LH, Niskanen L, Linke I Hedrer T. Nikon A. Lucan ‘mak! K, Dahil B, de Fae U, Merlin C, Kale BE. Wests PO, Bpck TE: Elect of sangiotensin-converting- enzyme inhibition Soapiehd eas Gaeetal Wanapy oe pets: the Copel Preven sion: the Captopil Prevention Project (CAPPP) randomaied tial Lancet 5201 1-616, 1990 9, Tt Pahor M, Byington DAN Garis R Stroll C. Srl F: Qutcame rests the Fisinopel Venus Andodipine Cantovascult Evers Raeerized Train patients with hypertension and NIDDM [Dinars Ca vont 28 eg 200i aur‘Therapeutic benefits of ACE inhibitors Diabetes Cae 21:597-008, 1998, 10. Eficacy f atenolol and capopsi in eeae- ing rk of macrovascular and mirovascu lar complications in type 2 diabates: UKPDS 49. BM'317:715-720, 1908 11, Hansson L, Lindholm LH. Ekbom 1. Dao B Lank I. Schersien B, Wesier PO. Heiner, de Faire U: Randornise tial of fold and new antihypertensive drugs i elder patierss: cardiovascular metality and morbidity. the Swedish Trl in Old Patienis With Hypertesion-2 study Lanes 3641751-1756, 1999, 12. WusufS, Poo R. Leis | Celine Sight Beta blockade during andar myorard infarction: an overview ofthe randori tial. Png Candinase De 27385-2171, 1985, 13, Cochran WG: Some methods fr srength- ening the common ehi-sue tests Bio- tates 1417-181, 1 14 Nathan DME Some answers, moe corto- ery tor UKPDS: Untied Kings Prospecsve Diabetes Sc Lane 352852 33.1908 15, Blumenfeld i, Seley JE. Mann S, Bragat Fu 18 A. Marion RPecker MS, Sotelo J, August B Pickering TG, Lavagh JH: Beta-ackenergic receptor blockade as a therapeutic approach for suppressing the renin. Angiotensin-aldosterone system in nor motenave and hypertensive subjects. Aim J ‘Hypertens 12451-4839, 1999 ‘Brges AB, Melaren M, Belch II: A com. parative study of captopril and enalapril on endothelial cell funetion in congestive heart faire patients. Argily46:811-817, 1995 Schindler B, Dinarello CA, Koch KM: jotersin-converting- enzyme inhibitors supe sha of ane er tor and interleukin 1 by human peripheral blood mononuclear cells. Cytokine 7526 533, 1995 a ‘Oshima, Ogawa H, Micuna ¥, Yamashita S. Noda K, Sata T. Sumida H. Suefuj H. ‘aikitaK, Sorina H, Yasue H: The of the angiotensin-converting enzyme Inhibitor imidapel on ‘activator inhibitor activity in patients with seuke myocardial infarction. Am Heart J 134:961-906, 1997 19, Vaughan DE, Rouleau JL. Ridker PM. Arnold IM, Menapace Fl. Plofer MA‘ Efects of ramipril on plasma itinaytc balance in patients with acute anteice laection: HEART Stay kes tgatrs. Cirulation 96:442-447, 1997 20, Heart Outcomes Prevention Evaluation Stuy Investors: les ofan anger cenveeing reve iubter. raise ‘crcionaseular events in high rok N Eig Mat'524:145-158: 2000 21. 1997 Joint National Comittee: The Sixth Report ofthe Join National Comamitee on Prevention. Detection. Evaluation. and ‘ieatment of High Blood Pressure. Arch dovern Med 157:2413-2446, 1997 22, Davis BRL Cutle JA, Gordon DI, Furberg CCD, Wright IT, Cushman WC, Grimm RH. Laos | Whelton PX Perry HM, Alder- sman Mil, Ford CE. Opa. Francis C, Proschan M, Pres S. Back HR, Hawkins CCM: Rationale andl desig fr the Antiby- peterate ancl Lipid Leng ete ‘To Prevert Heart Attack “Tal (ALLHAT) ‘Aan Hypertens 9342-900, 1996 TamCaxvmtinam 5/5ACE Inhibitors and Survival of Hemodialysis Patients ‘Shai Efrat, MO, Ronit Zaidenstein, MD, Vietor Dishy, MD, tia Beberashvii, MD, ‘Moshe Sharist, MD, Zhan Averbukh, MD, Ahuva Golk, MD, and Jashua Weissgaten, MD ‘= Background: Cardiovascular dnaane in leading cause of death in patients with enc-atage renal disease (ESRD). teparenain Ws maj a ate fs cariovncae compleatons i ae poten. Angetnai converting ‘enzyme (ACE) inhibitors are an effective treatment for hypertension in patients with ESRD and are known 13 Improve prognosis in patients with chronic renal failure. We investigated thei effect on moriaty in patients undergoing long-term hemodialysis therapy. Methods; Clinical data for patients on hemodialysis therapy between ‘1084 anc 2000 were reviewed. Patients ware Qroupad sccerding to whether they had bese tested with ACE inhibitors. Results: Slaty patients had been weated with ACE Inhibtors (weated group) and 6 patients Rad not {untreated group). Bioad pressure reduction was not nignificanty different between the wrested and unurested ‘groups. Nevertheless, the teated group withthe untreated group. morality was decreased signin {nthe treated group, with a risk reduction of $2% (rate ratio [RR], 0482: confidence interval [Ci]. 0.25 10ST: P= (0.0018). tn weated patients 65 years or younger, the absolute Fisk reduction of mortality was 79% (RR O.21T; CL 0.08 1018.58; P< 0.0008). Conclusion; Akhough further research i needed, these pretiminary findings suggest that ACE Wnibitars, Independently of their Antihypertensive elfect, may dramatically reduce mortality among chronic ‘hemodialysis patients 65 years or younger. Am J Kidney Dis 40:102)-1029 ‘© 2002 by the National Kidney Foundation, nc. INDEX WORDS: Hypertension: end-stage renal disease (ESRD) nemodistysis (MD). angiotensin converting enzyme (ACE) intubliors: survival, Editorial, p. 1100 ARDIOVASCULAR disease is a leading cause of morality in paticnis with end- stage renal disease (ESRD), accounting for 30% to S086 of all deaths.’ Hypertension is a major risk factor for candiovascular complications in both the general popelation and patients undergo- ing chronic hemodialysis therapy.' The malifac- torial pathogenesis of hypertension in patients with ESRD includes volume expansion,®? an increase in renin-angiotensin-aldosterone activt- ty, increased sympathetic activity,” impaired en- dotheial function," and byperparathyroidise.” ‘The precise contribution of the renin-angiotensin system is unknown Although in the general population, antihypertensive drugs of various s10ups positively affect the prognowis of patients ‘with hypertension, in high-risk populations the prognosis may be improved additionally by an- piotensin-converting enzyme (ACE) inhibitor." ‘Studies have established the effectiveness of ACE inhibitors tn the treatment of ESRD-related hypertension.!2!" However, there is 0 84 mm Hg: F< 0.004) 2/7ACE NMIBITORS IN HEMODIALYSIS 02s ‘Table 1. Basetine Demographic, Clinical, and Tresiment Characteristics of Patents Treated or Untreated With ACE Inhibitors ‘Urata n= 66 5962138 ao 36 (63) ome nes os 1302 O48 400 oz 409 02 or on 30 0) os ia) os ‘seo oe 2a) © 208 sien 3/7 noe ® 1303) on Blochemes! anc einscal parameters ‘Serum sumin (gist) az Hamaglots (gi) m1 ‘Systolc biood presse (re rg) waa 5231 Diastate bioad pressure (mH) raq= 14 43 = 108 NOTE. Vitues expressed as number (percend or mean = $0. Fer conversion of afiuenin or hemagistin to SI wrt, ‘musiiy by 10. during the follow-up period. Mean systolic Mood (143 * 18:9 compared with 132.5 + 21.4 mm pressure, although similar in the two groups at Hg: P< 0.013) the beginning of hemodialysis therapy, washigher Use of calcium channe! blockers and f-block- in the treated group during the follow-up period ef was similar in the (wo groups. a-lBlocker ‘Table 2. Mortality and Blochemical snd Clini! Parameters During Follow-Up of Patents Treated or Untreated ‘With ACE nhebitors Charatan [Urea 66) Treas 0) & ‘Serum sibumin (g/L) oa aes03 oss em oglotin (gis) oa Has ase [Erytvapoctn dose (Ues) ant one ‘Sytote blood pressure (mer Hg) a4 ants (Diastosebibod pressure (mr Hg) ae anos naw om oss (coment dea (Carsovescaat wen sa ‘coos ‘ntecson, 40m ray ass? ‘One wen 007) 15s NOTE. Valueh anpresied ai murrber (percent) or mean + SD For concemion of staumin oF hemogibin to St unit, mai ty 10.1026 were administered to more patients in the treated ‘group (48% compared with 22%; P < 0.012). ‘Treatment with ACE inhibitors was indepen dently associated with reduced all-cause mortal- ity (RR, 0.482; CI, 0.25 tw 0.91: P< 0.0019) by the Cox proportional hazards regression model, {In addition, other parameters included in the Cox [Proportional hazards regression model that were independently associated with mortality are age (U0 years; RR, 1.52;Cl, 141 to 1.67; P< 0.001), insulin-treated diabetes mellimus (RR. 1.86. CL LS1 to 223; P< 0001). and) non-insulin- treated diabetes mellitus (RR, 1.S1; Cl, 1.04 to 1.78; P < 0.08), Kaplan-Meier survival curves {or the treated and untreated groups are shown int Fig 1. The reduction in mortality ia patients treated with ACE inhibitors was caused mainly bby adecrease in cardiovascular death, including strokes, myocantial infarctions, heart failure, and peripheral vascular discase complications. Five patients (8%) in the treated group and 19 patients (29%) in the untreated group ched of candiowanc- Jar causes (P < 02003: Table 2) ‘When patients were subsivided om the basis of age (S65 years, 64 paticnts, >45 year, 62 ‘patients, it was found that at the beginning of dialysis therapy, the older subgroup had signifi scanily greater incidences of ischemic heart dis- cease (P < 0.054), cerebrovascular discase (P< 10.002), and peripheral vascular disease (P< 10.039} than younger patients. Mare patients were treated with ACE inhibitors in the older group ‘with the younger group: 66% versus 39% (P< 02006), respectively. Using the same Cox proportional hazards regression mode! for the group of patients 65 years and younger and the group of patients older than 65 years. it was found that treatment of patients 65 years of younger with ACE inhibitors xignificantly im- ‘Proved survival. yielding a 79% risk reduction An mortality relative to untreated patients younger than 65 years (RR, 0.211; Ci. 0.08 to 0.58: P< 0.0006). No effect of ACE-inhibitor treatment ox mortality could be shown in the okler group (Fig 2). Im the subgroup of patients older than 65 Years, there was a trend towand a reductior ‘mortality in patients treated with blocker the difference between these patients and 1 in the untreated older group was not significa ACE inhibitors can limit the detrimental effect. of angiotensin II om the cardiovascular system and kidneys, ameliorating functional and strec- tural changes produced by progressive renal in- sufficiency. Clinical trials in patients both with and without diahetes indicate a favorable effect of ACE inhibitors in delaying the progression of renal disease * Moreover, the Heart Outcome Prevention Evaluation study showed a decrease jn mortality associated with treatment with the ACE inhibitor ramipal in a subgroup of paticats 4/7ACE INHIBITORS IN HEMODIALYSES the effect of ACE inhibitors on mortality in chronic hemodialysis patients. Results of this retroprospective study show “Moreover, patients treated with ACE inhibitors ‘had a higher rate of concomitant treatment with vacblockers and morc LVH at baseline, possibly reflecting more pronounced hypertension. It is likely that ACE inhibitors exert additional cffects con the heart and vasculature in addition to reduc ing blood pressure. The Trial on Reversing Endo- thelial Dysfunction” showed that in nomoten- sive patients, treatment with the ACE inhibitor ‘quinapril reduce proliferation af smooth muscle, ‘of atherosclerotic plaques, and LVH and enhance fibrinolysis2° However, in the Simvastatin’ Enalapril Coronary Atherosclerosis Trial, no bea- ficial angiographic effect on the progression of existing atherosclerotic plaques was observed in /patients treated with an ACE inhibitor or a sta- tin? Similar findings were reported by MacMa- bom et a2 ‘LV in patients with ESRD is an independent tisk factor for cardiovascular diseases. Hypenten- som and anemia in dialysis patients are major risk factors for the development and progression. of LVHL In our study. 82% of patients under- went cchocandiography during the first yeat, but ‘only 17% underwent echocardiography a sccond time during the follow-up period: therefore, ao data are available on the effect of ACE imhibutors reparis, "as in our shidy, no stich effect was observed. Although calcium channe! blockers had ne ‘ar ‘effcct on survival in our data, very recently 2. heneficial effect of these agents on mortality im ‘hemondialysis paticnts was reporied by Bryan ct ‘al Conversely. a beneficial effect on survival of sis paticats with ACE inhibitors and ‘no effect of calcium channel Ihlockers was re- ported by Alain et a™ Itshould be noted that in ‘the report of Kestcabauim et al™ 27% of the study were of African-American ori- gin, whereas in the report by Guerin et al™ and ‘our study, there were no black patients. The sponse to therapy is different between ethnic soup." Lower plasma renin Kevels and a ‘better response to treatment with calcium chan- ‘nel blockers than ACE inhibitors and f-blockers, ‘in blacks have been reported. *"""* When our patients were scparated into twoage groups, we found that in those 65 years or ‘younger, treatment with ACE inhibitors reduced he mortality rate by 79%, No such differesce ‘was observed in the older group. These patients drug addition, no data are available for other pe tially imporiant end points, such as progres 5/7‘of LVH, congestive heart failure, number of ions, and quality of life. ‘A prospective study may require the recruit: ment of 400 hemodialysis patients (200 patients in cach group) and 3 years of follow-up to detcet 30% improvement in survival among patients treated with ACE inhibitors, with a power of 10% aid a8 cof 0.05 (assuming a dropost rate of 20%), However, recruitment to stich a staty muy be difficult because patients with LVH or heart failure at entry to dhalysis therapy [probably should be treated with ACE inhibitors, ‘thas significantly limiting the number of patents ‘available to this study, Nevertheless, the dra- rmutic reduction in mortality observed in our treated younger age group warrants a prospective study on the effects af ACE inhibitors in patients ‘on chronic hemodialysis therapy. ACKNOWLEDGMENT ‘Te autos thank Peal Lilon, Ss, from dae Laboratory ‘of Statistic, Department of Mathematacs Tel Avy Univer “Wty for aaintance with stats anaes REFERENCES 1 Levey AS, Beto JA. Coronado BEL et sli Contain ‘te epademi of canhovascular diease an chon ral ‘duvease: What do we know? What do we tel 10 leurn? ‘Where do we go ftom here? National Foundation Tash Purce on Canhownct Danse, Am J Kidey Dis 12:30, (998 12 Abesham PA, Opel JA, Keshav PR et at Mody und spaces ad Heead fressate os Reemakalvas putas shrimp areeiostion ch anes math eryirepocetn Aum J Kadney Dis 1640446, 1990 3 Lusk Al, Glades U, Kenan J, et bine of ‘mteralyes weaght gm on Nw peesse om emonkaby Patents. Bod Rail 12:259-266, 198 “A Schalchanyp MA, Beevers DG, Neigps ID, etl: Hype semiotic renal falar: Ar abnormal relations ‘berween sodum and the renieangioienn system. Am J Med S8:379-990, 1973 ‘3. Convene KL Jacobsen TN, Tou IRD, tal: Syrpa- ‘teaie evcemtinty to patent cheonie renal ative. [NEagl J Med 327-191-1918, 1996 (6 Martens BA. Kets DE: Role of intrarenal elite. lin in the generation and maintenance of hypetemson ‘Miner Electrolyte Mea 21342-3532, 1995 17, Sanuk N. Matsumoto H. Miyauchi T. et at Enmdoche- ‘un 3 concentrations in neman plasma: The increaeed concen: (airs in patient ndrgoing Biochem Bio ‘ys Res Commis 169-800-415, 1990 1K Vallance P. Leone A. Calver A. Colter 3. Moncada 8: ‘Accummilsion ef an endogenous inhibitor of mitic aide ‘then im conic rena ature, Lancet 339-592:575, 1992 9 Raise AE. BesfondL. Simpaon AW: Hyperparatyrid: EFRATIET AL, seo. platelet miracle cab a ypc i trek rena ale Ky at 1170.70, 1988 10. Meson tits Li, Hoon, at Random Aue lof ed al mew aiyperiemas drug eds avents Cardovaccuar may and meaty The Swe {oh Teal i OA Fanon Wi ypernmnn 2 Sdy Lact SSLITSI-1736, 1999 11 The Heat Ohtcomes Prevention Evasion Stady Aevesnganes Hof an angering eae thee, Cr ‘Basen Ning} Mea A314, 2000 12. Kelly X, Duyle GD, Carmody M. Gover DR. Coor Fer WD Plumas bp ala andes raat tm sen fade ect of mex Be F Che Prarnacol 28791 780, 1. Fille ff, Bapet HC; bots Bt ab: Kineton safety, amd ts my of ranma ng tee nh tom tn hemodisy ed patents. Y Candowane Pharmaed 27 en, 1996 14 Mina SK, Kawab Thnk et: Prevalence f Dyperensi An 4 Memacjs popuiaion. Che Nephd SU TH 9 13, De Cavanagh EM, Fender 1. Cananque Feta ager evs of aman deems eaaap ated ser man salad erated malvinas. At Kiery Dre BALE 488. 1 16 Lopes Ger JM, Nene Peres Gates Be Blood server. ef verlag a ba tem pga ‘5 memo patent Kidney [nt Supp 8592 1908 17 Sao A, Pander JW, Sars Tbavelvemest of done sone iv Kft Yenc bypertopy of pies wi em ‘tage roa adare weed wath heme, Am Hyper: tem 2807-73, 199" 18, Sica DA, Gets T, Femundes A: Rabel sate 9. hae IF, Gctacan BIC. Poe J. Roach J, Yas: eenal imaaicsemy a preter of canden cular owt vomes an the ampact of ramen Tae HOPE rancheuzed ‘al Am beeen Med 1386255. 2001 120. Daupindas JT, Van Sanne JC Physiology principles and urea umetc modeling. in Dangirdas FT. Blake PO. tng ‘TS: Handbook of Diayats (od 3). Philadephia. PA Lippi: cot Willams Witkian 3001, ppl 29 721. Bases WH: BMDP Stisstcal Saftwase. Los Angeles CA, Univesity of Califenia Pose 1992 ‘22 Keirsapar AV. Joy MS. Hogan SL_ Falk Ri. Ca res RE: Ellect of ACE tithes ox dashes: and sonia: ‘eo chromic renal dnt: A systema: overeaw of rao ‘aed place coatotid wins. Am J Kadocs Des 35-695-707, co} ‘2A. Mancini. Henry GC. Macaya Cc st Anpitemin comvesing yee nbchaien wih queged improves endo (eked veces dpateacticn ts ae wh corey ery deste. The TREND (Teal on Reversing Bact Dyatinction) Stay. Cicalation 9425E-268, 1996 ‘2d Varin. Muider F, Taming Feta: Improvement of odbielt fmetion By chrome angiotemun converting {ye inition near faiues Roe of mire tate poate‘AGE INFIBITORS IN HEMODIALYSIS oid, dant sees ad Benya. Ceeultion 102381 ‘smceba protection, Circulation W:2056-2009, 194 26. Schuler B. Schaefer EWilter Kleiner D. ct ak may ‘Salon 102-748-1754, 2000 2K Machaon S, Sharpe N. Gamble Get al: Randi tend, placebo costrlied tnal ofthe angimemie-somvering uy inabwce. amp. ea patents wad coronary x thes fcclive arte @aease. Part 2 Colborne Recor ‘Group, Prevestion of Adheros lvoe Wak Remap J Ams Coll Canbel 36-438-443, 2000 29, Levin A: Aneenia and lft ventriclae hypetoghy n chronic knioey diseane populations: A seview of the coment toe of re eige Kida 81'S35-33, 2002 (supp 80} “30. Camels G Paola B. Delina R,Peloxo G. Res D, Molinan § Protomped therapy with ACE inhibeors induces a repression of left veanncular hypertmphy of dialyzed ‘remus patents imdependenty from bypotaaive ffs. ‘Am J Kidney Dis 3059-668, 1997 "MH, Onoyama K. Sanat T, Mosomara K, Fujshime M: Wenning of sem by anpotrmis cunveing 10 years of habit and >10 cigarettes daily) hypertensive patients (15 males and three females, aged 69 £3 years) on ACEI therapy (1 captopril and seven enalapril). Patients were randomly allocated to (wo treatmert arms. In one ‘arm, the patients (n= 10) initially received the addition of NAC (600-mg Li-d.) to the ACEI tegimen. In the other group (1 = 8}, the patients remained only on ACEI, After 21 days, the therapeutic patterns were crossed, The first group received only ACEI, and the second group received ACE and NAC and completed other 21-day treatment period. We cvaluate the effect of NAC on each patient by ambulatory blood pressure monitoring (ABPM), performed at the end of each therapeutic regimen. A significant decrease in systolic and diastolic 24-h blood pressure (24 BP) and daytime BP (dtBP) was achieved with the combination af ACEI and NAC (ACEL+ NAC) when compared to the period with only ACEI: 24 MBP = 146.1 44.2 vs 137 43.1 (p <0.05) and 89.228 vs 835+ 3.7 mmblg (p= 0.01). DeBP: 149.7 4 $46 vs 141 + 3,7 and 92.1 44 vs 8643.2 (both, p < 0.05). No significant difference was ‘observed in night-time BP (ntBP). The NAC effect was not statistically different for the two ACEIs. In conclusion, the addition of NAC to an ACED potentiates its antihypertensive effect during 24%BP and KBP in smoker hypertensives, This effect may be mediated by an NO-dependent mechani sma, probably through the protective effect of NAC on NO oxidation. Key words: ACE inhibitors, Inypertension N= ‘acetyleysteine, nitric oxide, smoking. 2/6 INTRODUCTION acetylcholine, through an NO-dependent mechanism [7] ‘There is some evidence that NO participates in the Downloaded by [University of California, San Diego] at 09:17 06 December 2015 It is well known that endothelium plays a key role in different biologic functions, and blood pressure (BP) comtrol is one of the most relevant. This function is mediated by several vasoactive substances, such as cendothelin-I. prostacyclin or nitric oxide (NO) [1]. NO is potent endogenous agent released by endothelial cells in response to different physical and hormonal factors (2. 3}. Several studies have demonstrated the participation of NO in BP control, and subsequently its role in the pathogenesis of arterial hypertension [4]. It has been ‘suggested that the presence of tissue sulthydey! (SH) groups is necessary for the nitrovasodilators-induced relaxation [5]. In fact, SM group donors may be as crucial factors in the guanilate-cyelase sctivation induced by ‘organic nitrates and NO [6]. SH group donors, such as thiosalicylic acid or Neacetyleysteine (NAC). have been demonstrated to potentiate the hypotensive effect of (© 2002 Taylor & Francis on licence from Blood Prevure, ESSN O4a705U ‘antihypertensive effect of the angiotensin-converting ‘enzyme inhibitors (ACEIs) [8]. Therefore, since the hypotensive action of ACEIs seems to be at least partially mediated by NO, SH group donors may enhance the antihypertensive effect of these drugs. ‘There is still controversy over whether endothelial function is impaired in essestial hypertension [9, 10 ‘Although impairment of NO synthesis or increased inactivation of NO may account for the increased peripheral vascular tone associated with hypertension 11, 12] and hypertensive patients frequently exbibit an ‘inmpained endothelial function [13-17]. endothelial func- tion is not universally altered in essential hypertensives as, ‘Cockeroft ef al. described {18}. Therefore. the effect of an increased NO availability ia general hypertensive population could be scarce or even mull if the endothelial function is preserved. The effect of SH group donors may BLOOD PRESSURE: 2002Downloaded by [University of California, San Diego] at 09:17:06 December 2015 236 V. Barrios or a bbe especially useful in hypertensive patients with endothelial dysfunction. Since cigarette smoking may induce or increase endothelial dysfunction (19-21), SH group donors may be useful for potentiating the antihypertensive effect of ACEIs in smoker hypertensives through an NO-dependent mechanism, Thus, we ainsed to investigate the potential effect of the addition of NAC (600 mg Lid) to ACEI therapy in a smoker hypertensive Population. PATIENTS AND METHODS Inclusion and exelusion criteria ‘The inclusion criteria were: essential hypertension, an insufficient BP cootrol with an ACEI-based monatherapy during the last 3 months, a history of active smoking for more than 10 years asd a consumption of more than 10 cigarettes daily during the last year. On the other hand, the exclusion criteria were: a body mass index higher than 30 kg/m”; cardiac rhythm disturbances that may impede a fight ambulatory BP monitoring (ABPM) reading (such as atrial fibrillation, atrioventricular block or ventricular ahythenia); moderate of severe chronic obstructive ‘pulmonary disease; secondary hypertension: renal insuf- ficiency (serum ercalinine >1.4 mg/dl); significant hep- atic dysfunction or any other severe chronic disease: and the use of any drug that may interfere with ACEI or NAC. ‘The recruited patients were studied for 3 weeks prior to the allocation, to confirm the inadequate BP control and 10 ensure a good treatment compliance (>80%) with the ACEL Design ‘After an informed consent was obtained from all the selected patients, they were randomly allocated to two arms. The design of the study was an open within patient erossover study. In one arm (group A), the patients initially received ACEI + NAC (600 mg tid) during a 21-day period, at the end of which a 24-h ABPM was performed. After a S-day blanking period, patients changed to ACEI therapy and completed another 21-day ‘treatment period, A new 24-h ABPM was performed after this regimen with the ACEI only. In the other arm (group B), the patients were initially on ACEL and afterwards ‘crossed to. ACEI + NAC. The allocation of patients in two ams of different weatment patterns allowed ws to minimize the potential sequence effect. The results af two 24-h ABPM readings (ACEI vs ACEI + NAC) were compared, After both weatment periods, 4 clinical assessnent, with special attention to adverse events and jcntial concomilant medication, was completed. The study was approved by the Ethics Commitee of Hospital Ramin y Cajal BL000 PRESSURE 2002 ABPM ‘The ABPM device was a Spacelab 90207 (Redmond. WA), with readings each 15min in the daytime (08.00 22.00h) and 20min at night (22.00-08.00h). The variables assessed by ABPM were daytime, night-time. and 24-h systolic (SBP) and diastolic BP (DBP) after each tueatment period. The results were analyzed as a within patient comparison. Patients; baseline characteristics Eighicen gride I or II hypertensive patients were included im this study: 15 males and three females with an age of 69.45 years. All the patients were under ACEI therapy. LL of them (61%) with captopril (50mg bid.) and the remaining seven with enalapril (20mg 0.4). The mean time of the history of hypertension was 9+ 4 years. The mean duration of smoking was 20 + 13 years with a mean af 18 + § cigarettes daily. Ten patients were included in group A and eight in group B, Previous to each treatment period. office SBP and DBP were similar in both groups. The demographic and clinical characteristics of study population are expressed in Table E ‘Statistics Homogeneity of the study population was verified by an analysis of variance (ANOVA). Distributional assump- tion of normality was assessed by the Kolmogoray— Smimov test. ABMP changes in BP after cach treatment were assessed using ANOVA for a crossover design Comparison of ABPM measurements was ¢-—~1 ~t using the paired Student ‘test. Multivar methods were applied to evaluate event 3/6 factors, The statistical program SPSS w, calculations, A bilateral statistical significance nevet of = 0,05 was accepted. With this a-value, the sample size of this study give us an 80% power to detect the statistical significance by 5% of BP reductions caused by the NAC addition to the ACE, in a within patient crossover design study. Data obtained from ABPM expressed as mean +t SD for the different periods. RESULTS Mean follow-up for both treatment periods was 20: 3 days. The ABPM results showed significant reductions in systolic and diastolic 24hBP ax well as diBP in the ACEI +NAC period compared to ACEI alone. After ACEL+NAC, reductions of 90435 and 57+ 2d4mmHg were observed in systolic and diastolic DANBP: 146.14 4.2 vs 137 43.1, p < 005: and 89.2 + 2.4 vs83.5 ¢ 3.7, p =0.01. IndtBP, BP reduced 8.7 + 3.9 and 6.1 + 2.6 mmHg: dtBP: 149.7 + 5.6 ys 141 + 3.7 and 92.1 se 4 vw 86 3.2 mmiblg, both p < 0.05. On the other hand, no significant differences were observed in ntBP