Are Aall ACE Iinhibitors ACE Ace Iin Rreducing Bblood pPressure?
N Manassiev, J Vidal-Alaball, B Porter
Nick Manassiev, Josep Vidal-Alaball, Benjamin Porter
Nick 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 Worcestershire Royal Hospital, Worcester, UK
Background.
Hypertension is a common condition and its prevalence increases with age.[1],[2] (1, 2). It has been shown that hypertension is a risk factor for stroke, myocardial infarction (MI), renal failure, congestive heart failure, and dementia. The treatment of hypertension leads to decreased incidence of cardiovascular events and prolongs life. [3](3). The association between stroke and hypertension is stronger than that of coronary vascular disease and hypertension.[4] (4). It is currently recommended that blood pressure should be treated and the lower the blood pressure, the better.[5] (5). For patients over 55 years old (the majority of hypertensive patients) treatment with thiazide/thiazide type diuretic or dihydropiridine calcium channel blocker is recommended, adding an Angiotensin Converting Enzyme inhibitor (ACEi) if a second drug is necessary. For patients younger than 55 years of age initial treatment with an ACEi is recommended.5, [6](5,6). ACEi’s (perindopril and ramipril) are also recommended by the Royal College of Physicians for secondary prevention of stroke.[7] (7). Previous literature has concluded that the effect of ACEi’s on blood pressure and stroke is a ‘class effect’.6 (6).
In 2006 in England in 2006 30.1 million prescriptions were issued for ACEi’s. The most commonly used 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 2002 and 2006 the prescription of these ACEi’s, as percentage of the total, increased with different pace depending on the preparations; whilst the usage of perindopril increased by 140% and ramipril by 111%, lisinopril only showed a 22% increase with enalapril decreasing in usage by 13%.[8] (8)
In this paper we examine whether the most commonly prescribed ACEi’s in England haveEngland have similar 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 to manufacturers of ACEi’s asking for detailed information. We looked for randomised controlled trials (RCT) published in English. We retrieved all relevant original publications and tried to establish if all four of the most commonly prescribed ACEi’s in the England were equally effective. The inclusion criteria were:
1) rRandom allocation of patients to either an ACEi or placebo
2) rRandom allocation of patients to regimens based on different classes of blood 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 disease oor renal disease were included. Trials that selected patients mainly on the basis of acute MI or heart failure were not included, as often they did not report the effects of treatment separately for hypertensive and non-hypertensive patients or the report is incomplete. Trials were required 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. Ramipril
No RCT comparing ramipril with placebo for treatment of hypertension and satisfying the inclusion criteria was identified.
We found one study, the HOPE study, [9](9), thatwhich compared ramipril with to a placebo treatment in patients older 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 the participants was 66 years with a mean follow-up of 5 years. There were significant reductions in 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 subgroup analyses showing that ramipril was effective in decreasing events in patients with and without hypertension, and with and without stroke at baseline.
2. Perindopril
There were no RCTs comparing perindopril with placebo that satisfied our inclusion criteria.
We found one paper, the PROGRESS trial,[10] (10), comparing perindopril, indapamide and placebo in the secondary prevention of stroke. It enrolled 6105 participants and randomised them as follows: 1770 to peridopril and indapamide, 1771 to double placebo, 1281 patient to perindopril and 1280 to single placebo. 40% of the patients had a history of hypertension. The mean age of the patients was 64 years and the mean follow-up was 3.9 years. Treatment with perindopril lead to a reduction in blood pressure of 5/3mmHg compared with the placebo 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 the perindopril and placebo groups. Perindopril was no more effective than placebo in both hypertensive and non-hypertensive patients at baseline. No effect on death rates was reported, presumably because there was none.
The widely quoted ASCOT trial[11] (11) tested amlodipine or a combination of amlodipine and perindopril versus atenolol or a combination of atenolol and bendrofluazide. The way the study reported its finding does not allow any conclusions to be drawn about the effects of perindopril on hypertension.
The EUROPA study[12] (12) compared perindopril with placebo in patients with stable coronary artery disease. In this study only patients with evidence of coronary artery disease were recruited. 6110 of the study participants received perindopril and 6108 received placebo. The mean age of the patients was 60 years and the mean follow-up period was 4.2 years. 27 % of the patients (1650 in the treatment and 1662 in the placebo group) had hypertension. Although the study reported that perindopril treatment was associated with a significant reduction in the combined end point of cardiovascular mortality, non-fatal MI and resuscitated cardiac arrest (8% vs. 9.9%; p=0·0003) in patients with stable coronary artery disease and without heart failure or notable hypertension, there was no significant difference 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. Lisinopril
We were unable to find any studies comparing lisinopril with placebo in the treatment of hypertension.
One large randomised controlled study, the ALLHAT[13] (13) trial, compared the use of lisinopril (9054 patients) with chlorthalidone (15225 patients) and amlodipine (9048 patients) for the treatment of hypertension. The mean patient age was 67 years with a mean follow up of 4.9 years. The primary outcome was defined as either combined fatal coronary heart disease (CHD) or nonfatal MI analysed by intention to treat. (this part re-worded. The same wording used as in the ALLHAT abstract). Secondary outcomes were all-cause mortality, fatal and nonfatal stroke, combined CHD and combined cardio vascular disease (CVD). 23% of patients had a history of MI or stroke, and 36% were diabetic. There were a number of sub-analyses conducted. The results showed demonstrated that there was no difference between lisinopril and chlorthalidone for the primary outcome or for the secondary outcomes of all-cause mortality and combined CHD. The lisinopril group had a 15% higher risk of stroke and 10% higher risk of combined CVD, both statistically significant. (p=0.02 and p=<0.001 respectively). The authors concluded that thiazide-type diuretics were superior to ACEi’s in preventing CVD and should be used as the first step in the treatment of hypertension.
One Swedish study conducted in 1999 [14] (14)compared the ACEi’s lisinopril or enalapril to conventional 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 of follow up was 4.5 years. The study randomised 2208 to the ACEi group, 2213 to conventional drugs group and 2196 to the calcium antagonist group. There was no statistically significant 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 is not possible to draw any conclusions about the individual effects of lisinopril.
4. Enalapril
We did not find a randomised control trial meeting our inclusion criteria that compared enalapril and placebo for the treatment of hypertension.
The Swedish study,14 (14), mentioned previously, reported that lisinopril and enalapril were equivalent 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 to draw any conclusion about the effect of enalapril.
A further study[15] (15) randomised 3044 patients to receive an ACEi and 3039 to receive a diuretic. The mean age of the participants was 72 years and the follow-up lasted a median of 4.1 years. The patients were relatively low risk, with only 8% having CHD, 5% cerebrovascular disease and 7% being current smokers. The recommended treatment agents were 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 cause mortality (1.6% and 1.7%; p=0.27,), and stroke (0.92% and 0.88%; p=0.91) between the ACEi 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 on the different types of ACEi and diuretic and it is therefore not possible to draw any conclusions about enalapril.
Conclusions:
We did not find any head-to-head studies directly comparing the main four ACEi’s more commonly prescribed in England.
There is no evidence10,11,12 ( 10, 11, 12) that perindopril improves mortality or stroke rate in patients with 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 medication to either placebo or another blood pressure lowering agent.
There is some evidence9 (9) that Ramipril may be better than placebo for the treatment of hypertension in high risk patients. The evidence is indirect and difficult to quantify because of the way the study has been reported and furthermore, because the treatment of hypertension and 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 is for lisinopril (13).13 It has been shown that lisinopril is as effective as thiazide diuretics regarding total mortality, but inferior regarding prevention of stroke.
Discussion
ACEi’s are drugs approved for the treatment of hypertension. However, at the time of regulatory approval, it is not clear whether a short term decrease in blood pressure would translate 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 of hypertension by national guidelines,5,6, (5,6,[16] 16), despite the fact that evidence for the recommendation (other than lisinopril) is either lacking or unconvincing. Surprisingly, the recommendations do not distinguish between different ACEi’s, even though there is no evidence that either perindopril or enalapril improve stroke rates in people with hypertension. Inexplicably, the National Clinical Guidelines for Stroke7 (7) specifically recommends perindopril for secondary prevention of stroke in patients with hypertension, when well conducted studies conclusively shows that perindopril has no effect on stroke (10,12).10,12 Perhaps the author’s of the guidelines were assuming a class effect present in all ACEi’s? However, a class effect does not always exist in similar groups of drugs (e.g. metoprolol[17] (17) vs. atenolol [18](18) and simvastatin[19] (19) vs. Pravastin. [20](20)). It should be noted that all papers reviewed other than the study conducted by Dahlof and colleagues11 (11) were published at the time of drawing the guidelines.
In diabetics, hypertension is a stronger risk factor than blood sugar levels. For this reason it seems reasonable to use only drugs proven for the treatment of hypertension and with proven beneficial renal effects. Only lisinopril has a licence for nephropathy and microalbuminuria in hypertensive Type 2 diabetics.
On the basis of the evidence presented, lisinopril is the only commonly used ACEi that can be clearly 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 clear evidence that perindopril is not effective and should not 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.
Word Count: 2097
Corresponding author: Dr Nick Manassiev
E-mail address: e-mail
References:
1. Burt VL, Whelton PK, Roccella EJ et all. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995; 25: 305-313
2. SIGN. Hypertension in older people. A national clinical guideline. 2001, page 3
3. Pearce KA, Furberg CD, Rushing J. Does antihypertensive treatment of the elderly prevent cardiovascular event or prolong life. Arch Fam Med 1995; 4: 943-950
4. MacMahon S, Peto R, Cutler J et all. Epidemiology: blood pressure, stroke and coronary heart disease. Lancet 1990; 335: 765-774
5. 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. J Hum Hyper 2004;18:139-185
6. The National Collaborating Centre for Chronic Conditions. Hypertension. Management of hypertension in adults in primary care: partial update of NICE Clinical Guideline 18. Royal College of Physicians, 2006
7. Intercollegiate Stroke Working Party. National Clinical Guidelines for Stroke. Royal College of Physician Press, Second Edition, 2004