Are all ACE inhibitors ace in treatment of essential hypertension?

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Abstract: ACE inhibitors (ACEi) are widely recommended and used for treatment of hypertension. There are number of ACEi to choose from. It make sense to use the one that that has been shown to be most effective in prevention of serious hypertension complication such as stroke. If there is more that one choice it make sense to use the one with lower acquisition cost. In this paper we are looking into the evidence for using ACEi as a first line treatment for hypertension and to try and find out which ACEi has been associated with the best clinical outcome. We found no long-term trials comparing ACEi and placebo for treatment of hypertension. We found no head-to-head studies directly comparing the main four ACEi’s, commonly prescribed in England. On the basis of the evidence presented, lisinopril is the only commonly used ACEi that can be considered a first line treatment for hypertension. There is some evidence for ramipril, although this is not as strong. There is no substantial evidence of the effectiveness of enalapril and in the presence of a proven treatment (lisinopril) it makes no sense to use it for the treatment of hypertension. There is no evidence that perindopril improves mortality or stroke rate in patients with hypertension. Perindopril is no better than placebo for treatment of patients with previous TIA or stroke.

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Are all ACE inhibitors ace in treatment of essential hypertension?

  1. 1. Are all ACE inhibitors ace in treatment of essential hypertension?Nik Manassiev, Josep Vidal-Alaball, Benjamin PorterNik Manassiev, Goodrest Croft Surgery, 1 Goodrest Croft, Yardley Wood, Birmingham, UK;Josep Vidal-Alaball, Department of Primary Care and Public Health, School of Medicine,Cardiff University, Wales, UK; Benjamin Porter, FY1, Worcestershire Royal Hospital,Charles Hastings’s Way, Newtown Road, Worcester, WR5 4DDAbstract: ACE inhibitors (ACEi) are widely recommended and used for treatment ofhypertension. There are number of ACEi to choose from. It make sense to use the one thatthat has been shown to be most effective in prevention of serious hypertension complicationsuch as stroke. If there is more that one choice it make sense to use the one with loweracquisition cost. In this paper we are looking into the evidence for using ACEi as a first linetreatment for hypertension and to try and find out which ACEi has been associated with thebest clinical outcome. We found no long-term trials comparing ACEi and placebo fortreatment of hypertension. We found no head-to-head studies directly comparing the mainfour ACEi’s, commonly prescribed in England. On the basis of the evidence presented,lisinopril is the only commonly used ACEi that can be considered a first line treatment forhypertension. There is some evidence for ramipril, although this is not as strong. There is nosubstantial evidence of the effectiveness of enalapril and in the presence of a proven treatment(lisinopril) it makes no sense to use it for the treatment of hypertension. There is no evidencethat perindopril improves mortality or stroke rate in patients with hypertension. Perindopril isno better than placebo for treatment of patients with previous TIA or stroke.Background.Hypertension is a common condition and its prevalence increases with age (1, 2). It has beenshown that hypertension is a risk factor for stroke, myocardial infarction (MI), renal failure,congestive heart failure, and dementia. The treatment of hypertension leads to decreasedincidence of cardiovascular events and prolongs life (3). The association between stroke andhypertension is stronger than that of coronary vascular disease and hypertension (4). It iscurrently recommended that blood pressure should be treated and the lower the bloodpressure, the better (5). For patients over 55 years old (the majority of hypertensive patients)treatment with thiazide/thiazide type diuretic or dihydropiridine calcium channel blocker isrecommended, adding an Angiotensin Converting Enzyme inhibitor (ACEi) if a second drugis necessary. For patients younger than 55 years of age initial treatment with an ACEi isrecommended (5,6). ACEi’s (perindopril and ramipril) are also recommended by the RoyalCollege of Physicians for secondary prevention of stroke (7). Previous literature hasconcluded that the effect of ACEi’s on blood pressure and stroke is a ‘class effect’ (6).In England in 2006 30.1 million prescriptions were issued for ACEi’s. The most commonlyused ACEi’s were ramipril (39.8%), lisinopril (25.2 %), perindopril (18.7%) and enalapril(9.9%). Together, these accounted for 93.6% of all ACEi’s prescribed in 2006. Between 2002and 2006 the prescription of these ACEi’s, as percentage of the total, increased with differentpace depending on the preparations; whilst the usage of perindopril increased by 140% andramipril by 111%, lisinopril only showed a 22% increase with enalapril decreasing in usageby 13%. (8)
  2. 2. In this paper we examine whether the most commonly prescribed ACEi’s in England havesimilar effects regarding treatment of hypertension and reducing the risk of stroke.Methods:We searched Medline and Embase from 1985 onwards and searched all the relevant reviews,guidelines, policy statements and recommendations for references. We also wrote tomanufacturers of ACEi’s asking for detailed information. We looked for randomisedcontrolled trials (RCT) published in English. We retrieved all relevant original publicationsand tried to establish if all four of the most commonly prescribed ACEi’s in the England wereequally effective. The inclusion criteria were: 1) random allocation of patients to either anACEi or placebo 2) random allocation of patients to regimens based on different classes ofblood pressure lowering drugs that included an ACEi.Trials that included patients who were selected mainly on the basis of high blood pressure,diabetes mellitus, coronary heart disease, cerebrovascular disease, peripheral vascular diseaseor renal disease were included. Trials that selected patients mainly on the basis of acute MI orheart failure were not included, as often they did not report the effects of treatment separatelyfor hypertensive and non-hypertensive patients or the report is incomplete. Trials wererequired to have at least 250 patients per group with a minimum duration of at least one year.Trials were required to report at least total mortality, stroke incidence and MI incidence.Results: 1. RamiprilNo RCT comparing ramipril with placebo for treatment of hypertension and satisfying theinclusion criteria was identified.We found one study, the HOPE study (9), that compared ramipril with placebo in patientsolder than 55 with high risk for cardiovascular disease. The study randomised 9297 patients,47% of them had hypertension and 11% had stroke on enrolment. The mean age of theparticipants was 66 years with a mean follow-up of 5 years. There were significant reductionsin the rates of death of any cause (12.2% vs. 10.4%; p=0.005), death of cardiovascular causes(8.1% vs. 6.1%; p<0.001), MI (12.3% vs. 9.9%; p<0.001) and stroke (3.9% vs. 3.4%;p<0.001) in the group receiving ramipril. There were a number of pre-planned subgroupanalyses showing that ramipril was effective in decreasing events in patients with and withouthypertension, and with and without stroke at baseline. 2. PerindoprilThere were no RCTs comparing perindopril with placebo that satisfied our inclusion criteria.We found one paper, the PROGRESS trial (10), comparing perindopril, indapamide andplacebo in the secondary prevention of stroke. It enrolled 6105 participants and randomisedthem as follows: 1770 to peridopril and indapamide, 1771 to double placebo, 1281 patient toperindopril and 1280 to single placebo. 40% of the patients had a history of hypertension. Themean age of the patients was 64 years and the mean follow-up was 3.9 years. Treatment withperindopril lead to a reduction in blood pressure of 5/3mmHg compared with the placebo
  3. 3. group. There was no difference in the occurrence of stroke (157 [n=1281] vs. 165 [n=1280];p>0.6) or major cardiovascular events (227 [n=1281] vs. 237 [n=1280]; p>0.6) between theperindopril and placebo groups. Perindopril was no more effective than placebo in bothhypertensive and non-hypertensive patients at baseline. No effect on death rates was reported,presumably because there was none.The widely quoted ASCOT trial (11) tested amlodipine or a combination of amlodipine andperindopril versus atenolol or a combination of atenolol and bendrofluazide. The way thestudy reported its finding does not allow any conclusions to be drawn about the effects ofperindopril on hypertension.The EUROPA study (12) compared perindopril, 8 mg per day, with placebo in patients withstable coronary artery disease. In this study only patients with evidence of coronary arterydisease were recruited. 6110 of the study participants received perindopril and 6108 receivedplacebo. The mean age of the patients was 60 years and the mean follow-up period was 4.2years. 27 % of the patients (1650 in the treatment and 1662 in the placebo group) hadhypertension (blood pressure >190/95 or receiving antihypertensive treatment). Treatmentwith perindopril resulted in decrease of 5/2 mmHg in blood pressure in comparison withplacebo treatment. Although the study reported that perindopril treatment was associated witha significant reduction in the combined end point of cardiovascular mortality, non-fatal MIand resuscitated cardiac arrest (8% vs. 9.9%; p=0·0003) in patients with stable coronaryartery disease and without heart failure or notable hypertension, there was no significantdifference in reducing total mortality (6.1% vs. 6.9%; p=0.1) or stroke (1.6% vs. 1.7%)between treatment and placebo group respectively. 3. LisinoprilWe were unable to find any studies comparing lisinopril with placebo in the treatment ofhypertension.One large randomised controlled study, the ALLHAT (13) trial, compared lisinopril (9054patients) with chlorthalidone (15225 patients) and amlodipine (9048 patients) for thetreatment of hypertension. The mean patient age was 67 years with a mean follow up of 4.9years. The primary outcome was combined fatal coronary heart disease (CHD) or nonfatalMI analysed by intention to treat. Secondary outcomes were all-cause mortality, fatal andnonfatal stroke, combined CHD and combined cardio vascular disease (CVD). 23% ofpatients had a history of MI or stroke, and 36% were diabetic. There were a number of sub-analyses conducted. The results showed that there was no difference between lisinopril andchlorthalidone for the primary outcome or for the secondary outcomes of all-cause mortalityand combined CHD. The lisinopril group had a 15% higher risk of stroke and 10% higher riskof combined CVD, both statistically significant (p=0.02 and p=<0.001 respectively). Theauthors concluded that thiazide-type diuretics were superior to ACEi’s in preventing CVDand should be used as the first step in the treatment of hypertension.One Swedish study conducted in 1999 (14)compared the ACEi’s lisinopril or enalapril toconventional treatment (β-blocker and/or hydrochlorothyazide) or a calcium antagonist(felodipine or isradipine). The mean age of the patients was 76 years and the mean length offollow up was 4.5 years. The study randomised 2208 to the ACEi group, 2213 to conventionaldrugs group and 2196 to the calcium antagonist group. There was no statistically significant
  4. 4. difference in total mortality, cardiovascular mortality, MI or stroke between treatment groups.The study did not report the results according to individual treatment agents and therefore it isnot possible to draw any conclusions about the individual effects of lisinopril. 4. EnalaprilWe did not find a randomised control trial meeting our inclusion criteria that comparedenalapril and placebo for the treatment of hypertension.The Swedish study (14), mentioned previously, reported that lisinopril and enalapril wereequivalent to β-blockers, diuretics or calcium antagonists in treating hypertension. However,the results were not reported for individual medications and therefore it was not possible todraw any conclusion about the effect of enalapril.A further study (15) randomised 3044 patients to receive an ACEi and 3039 to receive adiuretic. The mean age of the participants was 72 years and the follow-up lasted a median of4.1 years. The patients were relatively low risk, with only 8% having CHD, 5%cerebrovascular disease and 7% being current smokers. The recommended treatment agentswere enalapril for the ACEi group and hydrochlorothiazide for the diuretic group. However,the choice of agent was left to the individual doctor. There was no difference in all causemortality (1.6% and 1.7%; p=0.27,), and stroke (0.92% and 0.88%; p=0.91) between theACEi group and the diuretic group respectively. There was a statistically significant 32%reduction in the rate of nonfatal MI in the ACEi group compared to the diuretic group(adjusted hazard ratio, 0.68; p=0.05). The authors did not publish how many patients were onthe different types of ACEi and diuretic and it is therefore not possible to draw anyconclusions about enalapril.Conclusions:We found no long-term trials comparing ACEi and placebo for treatment of hypertension.We found no head-to-head studies directly comparing the main four ACEi’s, commonlyprescribed in England.There is no evidence ( 10, 11, 12) that perindopril improves mortality or stroke rate in patientswith hypertension, or in patients with previous TIA or stroke in comparison to placebo.No inferences can be drawn about Enalapril as there are no studies comparing this medicationto either placebo or another blood pressure lowering agent.There is some evidence (9) that Ramipril may be better than placebo for the treatment ofhypertension in high risk patients. The evidence is indirect and difficult to quantify because ofthe way the study has been reported and furthermore, because the treatment of hypertensionand stroke prevention was not a primary or secondary outcome of the study.The strongest evidence we found about the use of ACEi’s for the treatment of hypertension isfor lisinopril (13). It has been shown that lisinopril is as effective as thiazide diureticsregarding total mortality, but inferior regarding prevention of stroke.
  5. 5. DiscussionACEi’s are drugs approved for the treatment of hypertension. However, at the time ofregulatory approval, it is not clear whether a short term decrease in blood pressure wouldtranslate into improvements in hard clinical outcomes, such as mortality rates and stroke rates.It is surprising therefore, to find that ACEi’s are recommended as the first line treatment ofhypertension by national guidelines (5,6, 16), despite the fact that evidence for therecommendation (other than lisinopril) is either lacking or unconvincing. Surprisingly, therecommendations do not distinguish between different ACEi’s, even though there is noevidence that either perindopril or enalapril improve stroke rates in people with hypertension.Inexplicably, the National Clinical Guidelines for Stroke (7) specifically recommendsperindopril for secondary prevention of stroke in patients with hypertension, when wellconducted studies conclusively shows that perindopril has no effect on stroke (10,12). Perhapsthe author’s of the guidelines were assuming a class effect present in all ACEi’s? However, aclass effect does not always exist in similar groups of drugs (e.g. metoprolol (17) vs. atenolol(18) and simvastatin (19) vs. pravastin (20)). It should be noted that all papers reviewed otherthan the study conducted by Dahlof and colleagues (11) were published at the time of drawingthe guidelines.In diabetics, hypertension is a stronger risk factor than blood sugar levels. For this reason itseems reasonable to use only drugs proven for the treatment of hypertension and with provenbeneficial renal effects. Only lisinopril has a licence for nephropathy and microalbuminuria inhypertensive Type 2 diabetics.On the basis of the evidence presented, lisinopril is the only commonly used ACEi that can beclearly considered a first line treatment for hypertension. There is some evidence for ramipril,although this is not as strong. There is no substantial evidence of the effectiveness of enalapriland in the presence of a proven treatment (lisinopril) it makes no sense to use it for thetreatment of hypertension. There is clear evidence that perindopril is not effective and shouldnot be used for treating hypertension. Furthermore, because (at the time of writing)perindopril is still on patent, it is over three times the cost of either ramipril or lisinopril.
  6. 6. References:1. Burt VL, Whelton PK, Roccella EJ et all. Prevalence of hypertension in the US adultpopulation. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995; 25: 305-3132. SIGN. Hypertension in older people. A national clinical guideline. 2001, page 33. Pearce KA, Furberg CD, Rushing J. Does antihypertensive treatment of the elderly preventcardiovascular event or prolong life. Arch Fam Med 1995; 4: 943-9504. MacMahon S, Peto R, Cutler J et all. Epidemiology: blood pressure, stroke and coronaryheart disease. Lancet 1990; 335: 765-7745. Williams B, Poulter NR, Brown MJ et all. Guidelines for management of hypertension:report of the fourth working party of the British Hypertension Society, 2004 – BHS IV. JHum Hyper 2004;18:139-1856. The National Collaborating Centre for Chronic Conditions. Hypertension. Management ofhypertension in adults in primary care: partial update of NICE Clinical Guideline 18. RoyalCollege of Physicians, 20067. Intercollegiate Stroke Working Party. National Clinical Guidelines for Stroke. RoyalCollege of Physician Press, Second Edition, 20048. David Cracknell, Office for National Statistics, personal communication 2007 9. The Heart Outcome Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl JMed 2000;342:145-5310. PROGRESS Collaborative group. Randomised trial of perindopril-based blood pressurelowering regimen among 6105 individuals with previous stroke or transient ischemic attack.Lancet 2001;358:1033-104111. Dahlof B, Sever PS, Poulter NR et al. Prevention of cardiovascular events with anantihypertensive regimen of amlodipine adding perindopril as required versus atenolol addingbendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial – bloodpressure lowering arm (ASCOT – BPLA): a multicentre randomised controlled trial. Lancet2005;366:895-90612. The EURopean trial On reduction of cardiac events with Perindopril in stable coronaryArtery disease Investigators. Efficacy of perindopril in reduction of cardiovascular eventsamong patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial ( the EUROPA study). Lancet 2003;362: 782-8813. The antihypertensive and lipid-lowering treatment to prevent heart attack trial(ALLHAT). Major outcomes in high-risk hypertensive patients randomised to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA 2002;288:2981-299714. Hansson L, Lindholm LH, Ekbom T et al. Randomised trial of old and newantihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the SwedishTrial in Old Patients with Hypertension-2 study. Lancet 1999;354:1751-5615. Wing LMH, Reid CM, Ryan P et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med2003;348:583-9216. JBS 2: Joint British Societies’ Guidelines on Prevention of Cardiovascular Disease inClinical Practice. Heart 2005;91:suppl V ( v1-v51)17. Wikstrand J, Warnold I, Olsson G, Tuomilehto J, Elmfeldt D, Berglund G. Primaryprevention with metoprolol in patients with hypertension. Mortality results from the MAPHYstudy. JAMA 1988;259:1976-82
  7. 7. 18 MRC Working Party. Medical research council trial of treatment of hypertension in olderadults: principal results. BMJ 1992;304:405-41219. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study ofcholesterol lowering with simvastatin in 20 536 high risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-2220. The ALLHAT Officers and coordinators for the ALLHAT collaborative research group.Major outcome in moderately hypercholesterolemic, hypertensive patients randomised topravastatin versus usual care. The Antihypertensive and Lipid Lowering Treatment to PreventHeart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998-3007WORD COUNT: 2076Corresponding author: Dr Nik Manassiev. E-mail address: d_manassieva@hotmail.comJanuary 2009

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