| | Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditionsPresented at the Sixtieth Annual Meeting of the Society for Vascular Surgery, Philadelphia, Pa, June 1-4, 2006. Received 30 May 2006; accepted 18 December 2006. ObjectivesThe Heart Protection Study (HPS) provides an opportunity to assess directly the effects of cholesterol-lowering therapy on major vascular events (defined as myocardial infarction, coronary death, stroke, or revascularization) in patients with peripheral arterial disease (PAD). In addition, the effects on peripheral vascular events (ie, non-coronary revascularization, aneurysm repairs, major amputations or PAD deaths) can be assessed. Methods6748 UK adults with PAD and 13,788 other high-risk participants were randomly allocated to receive 40 mg simvastatin daily or matching placebo, yielding an average LDL cholesterol difference of 1.0 mmol/L (39 mg/dL) during a mean of 5 years. ResultsFor participants with PAD, allocation to simvastatin was associated with a highly significant 22% (95% CI 15-29) relative reduction in the rate of first major vascular event following randomisation (895 [26.4%] simvastatin-allocated vs 1101 [32.7%] placebo-allocated; P < .0001), which was similar to that seen among the other high-risk participants. The absolute reduction in first major vascular event was 63 (SE 11) per 1000 patients with PAD and 50 (SE 7) per 1000 without pre-existing PAD. Overall, among all participants, there was a 16% (5-25) relative reduction in the rate of first peripheral vascular event following randomisation (479 [4.7%] simvastatin vs 561 [5.5%] placebo), largely irrespective of baseline LDL cholesterol and other factors. This effect chiefly reflects a 20% (8-31) relative reduction in non-coronary revascularization procedures (334 [3.3%] vs 415 [4.0%]; P = .002). ConclusionHPS demonstrates the benefits of cholesterol-lowering statin therapy in patients with PAD, regardless of their presenting cholesterol levels and other presenting features. Allocation to 40 mg simvastatin daily reduces the rate of first major vascular events by about one-quarter, and that of peripheral vascular events by about one-sixth, with large absolute benefits seen in participants with PAD because of their high vascular risk. Consequently, statin therapy should be considered routinely for all patients with PAD. Peripheral arterial disease (PAD) is a common condition, with a prevalence of up to 20% in populations aged over 65 years.1, 2, 3 It is associated with a marked increase in cardiovascular risk in patients both with and without co-existing coronary artery disease.4 Observational studies in different populations indicate a continuous, positive and log-linear relationship between coronary disease risk and blood cholesterol concentration that extends well below the range commonly seen in Western populations, without any definite threshold below which a lower concentration is not associated with lower risk.5, 6, 7, 8 The risk factors for coronary and peripheral arterial disease are similar, and higher cholesterol concentrations are associated with higher rates of peripheral arterial disease.9 Despite the high incidence of cardiovascular morbidity and mortality in patients with PAD, relatively few such patients had been included in previous randomized controlled trials of cholesterol-lowering statin therapy.10, 11, 12, 13, 14, 15 By contrast, the MRC/BHF Heart Protection Study (HPS) has demonstrated that lowering LDL cholesterol concentrations with 40 mg simvastatin daily produces substantial reductions in the rates of heart attacks, strokes, and revascularization procedures among a wide range of high-risk individuals, including the large numbers with PAD.16, 17, 18, 19 Despite this clear evidence of benefit, almost two-thirds of patients with PAD are still not receiving statin therapy.20 The aim of the present report is to provide more details from HPS about the benefits of cholesterol-lowering with statin therapy in patients with PAD. Patients and methods  Details of the study have been reported previously16, 17, 18, 19 (see also www.hpsinfo.org). In brief, men and women aged about 40-80 years with non-fasting blood total cholesterol concentrations of at least 3.5 mmol/L (135 mg/dL) were eligible provided they had a medical history of coronary disease, PAD, cerebrovascular disease, diabetes, or treated hypertension (if also male and aged at least 65 years). PAD was defined as a history of intermittent claudication (with or without supporting vascular investigations) or previous peripheral arterial revascularization procedure, amputation, or aneurysm repair. People were ineligible if their own doctor considered statin therapy to be clearly indicated or contraindicated, or if they had myocardial infarction, stroke or hospital admission for angina within the previous 6 months; chronic liver disease or evidence of abnormal liver function; severe renal disease or evidence of substantially impaired renal function; inflammatory muscle disease or evidence of muscle problems; concurrent treatment with ciclosporin, fibrates, or high-dose niacin; child-bearing potential; severe heart failure; or other conditions that might limit long-term compliance. Statistical analysis The main comparisons involved logrank analyses of the first occurrence of particular events during the scheduled treatment period after randomisation among all those allocated 40 mg simvastatin daily versus all those allocated matching placebo tablets (ie, intention-to-treat).21 These logrank analyses yielded both the event rate ratio and the test of statistical significance (two-sided probability value). Assessments of the effects of treatment in different prespecified subcategories of prior disease (including PAD) and of other presenting features were to be based on first major coronary events (defined as non-fatal myocardial infarction or death from coronary disease), and, particularly, on the even larger number of first major vascular events (defined as major coronary events, strokes of any type, and coronary or non-coronary revascularizations). Tests for heterogeneity or, if more appropriate, trend were to be used to determine whether the proportional effects observed in specific subcategories differed clearly from the overall effects (after due allowance for multiple comparisons and the exploratory nature of some analyses). Subsidiary comparisons included assessment of the effects of allocation to simvastatin not just on the rate of first major vascular events following randomisation, but also on the numbers of first and subsequent events during the scheduled treatment period, and of the effects on non-coronary vascular procedures (ie, carotid endarterectomy or angioplasty, other arterial grafts or angioplasty, and amputation). For the purposes of the present report, exploratory analyses were performed assessing the effects of statin allocation on peripheral vascular events (defined retrospectively as the first occurrence of a non-coronary revascularization, aneurysm repair, major amputation, or death from PAD). Role of the funding sources The investigators were responsible for the study design, data collection, data analysis, data interpretation, and writing of the report, independently of all funding sources. Results Between July 1994 and May 1997, 6748 people aged 40-80 years with PAD and a further 13,788 high-risk patients without diagnosed PAD were randomly allocated to receive 40 mg simvastatin daily or matching placebo tablets in a double-blind manner (and, separately, using a two-by-two factorial design, antioxidant vitamins or matching placebo capsules22). Among participants presenting with a history of PAD, 33% had undergone peripheral arterial surgery or angioplasty and 2% had had an amputation, while the remainder had symptomatic PAD. Of the trial participants with PAD, 60% had coronary heart disease (CHD), 8% had cerebrovascular disease, and 23% had diabetes (Table I). Compared with participants without PAD, those who had PAD were more likely to be current or ex cigarette smokers (84% vs 70%) and had slightly higher mean total and LDL cholesterol and triglycerides. Diabetes was less common in the PAD subgroup, largely due to the selective enrolment of almost 3000 diabetic patients who did not have overt occlusive arterial disease. The large size of the study (and the use of minimized randomisation23) produced good balance between the treatment groups among participants within both the PAD and non-PAD groups for the main prognostic features that were measured (and should have done likewise for those that were not). | | |  | Baseline Feature | Peripheral artery disease (n = 6748) | No peripheral artery disease (n = 13788) | |
|---|
| Age (years) | 64.5 (8.1) | 63.7(8.5) | | | Men | 5014(74%) | 10440(76%) | | | Smoking | | | | | Never regular | 1093(16%) | 4081(30%) | | | Ex-cigarette | 4258(63%) | 8191(59%) | | | Current | 1397(21%) | 1516(11%) | | | Vascular disease | | | | | Prior MI | 2372(35%) | 6138(45%) | | | Other CHD | 1675(25%) | 3201(23%) | | | Cerebrovascular | 521(8%) | 1299(9%) | | | Diabetes | 1579(23%) | 4384(32%) | | | Treated hypertension | 2898(43%) | 5559(40%) | | | Systolic BP (mmHg) | 146(24) | 143(23) | | | Diastolic BP (mmHg) | 81(13) | 82(12) | | | Body mass index (kg/m2) | 27.6(4.4) | 27.6(4.4) | | | Total cholesterol (mmol/L) | 6.0(1.05) | 5.8(0.99) | | | LDL cholesterol (mmol/L) | 3.5(0.86) | 3.3(0.80) | | | HDL cholesterol (mmol/L) | 1.04(0.32) | 1.07(0.33) | | | Triglycerides (mmol/L) | 2.2(1.42) | 2.0(1.34) | | | Apolipoprotein A1 (mg/dL) | 1.19(0.22) | 1.20(0.22) | | | Apolipoprotein B (mg/dL) | 1.17(0.24) | 1.13(0.23) | | | | |
Compliance and effect on blood lipids The mean duration of follow-up was 5.0 years for all randomized participants: 5.3 years for those who survived to the scheduled end of the study treatment and about half that for those who did not. Compliance at each follow-up was defined as at least 80% of the scheduled simvastatin or placebo tablets having been taken since the previous follow-up (based on questioning the participant and review of remaining calendar-packed tablets). Among all participants allocated 40 mg simvastatin daily, average statin use during the scheduled treatment period was 85% (with 82% compliant with their allocated simvastatin, 3% on non-study statin alone and 2% on both: Table II, online only). By contrast, amongst those allocated placebo, an average of 17% were taking non-study statin therapy during the study. This average absolute difference in statin use of 67% (85% minus 17%) between all participants allocated simvastatin and all those allocated placebo yielded an average difference in LDL cholesterol of 1.0 mmol/L (suggesting that actual use of 40 mg simvastatin would reduce LDL cholesterol by an average of about 1.5 mmol/L in this population). Non-study statin use in the placebo group was more common among those who already had diagnosed coronary disease at entry, were younger or had higher pre-treatment LDL cholesterol concentrations, but it was not influenced by the presence of PAD (Table II, online only). The average differences in plasma lipid concentrations during follow-up were similar in those with and without PAD at baseline. Effects on major vascular events in the presence and absence of PAD Overall, allocation to simvastatin produced a very highly significant 24% (95% CI 19-28; P < .0001) proportional reduction in the first occurrence of a major vascular event following randomisation (Fig 1). Among the participants with diagnosed PAD at study entry there was a highly significant 22% (15-29; P < .0001) proportional reduction in major vascular events, which was similar to the 25% (20-31; P < .0001) reduction among the other high-risk participants studied (heterogeneity P = .5) Similar proportional reductions were also observed among patients with or without PAD in the rates of first major coronary event, stroke, and revascularizations considered separately (Fig 1). The 24% (17-30; P < .0001) reduction in the rate of any revascularization procedure observed among all participants reflected a 30% (22-38; P < .0001) reduction in coronary revascularizations and a 16% (5-26; P = .006) reduction in non-coronary revascularizations (including amputations), with similar proportional reductions observed in those with and without PAD. The absolute reduction in major vascular events was somewhat greater in participants with PAD at baseline (63 [SE 11] per 1000) than in those without PAD (50 [SE 7] per 1000: Fig 2). This reflected a greater absolute reduction in revascularizations among participants with PAD (42 [SE 9] per 1000) than among those without PAD (19 [SE 5] per 1000). Effects on major vascular events in different circumstances among participants with PAD and other participants The extreme statistical significance of the overall reduction in the rate of first major vascular events (z-score = 9.3), and the large number of events on which it is based, allows reliable assessment of the effects of treatment in various different categories of patient. The relative risk reduction among participants with or without diagnosed PAD at study entry was about a quarter in each of the subcategories studied (Fig 3, Fig 4). In particular, among the 2701 patients with PAD but no pre-existing coronary disease, there was a significant 22% reduction in first major vascular events (327 [24.7%] simvastatin vs 420 [30.5%] placebo), which was similar to the effect in the other patients (heterogeneity P = .9: Fig 4). The proportional risk reductions among all 6748 participants with PAD also appeared to be about a quarter, irrespective of their history of other vascular disease, diabetes, sex, or age (Fig 3 and Fig 4). Most notably, the proportional reduction in risk did not appear to be materially influenced by the pre-treatment lipid concentrations. So, for example, there was a highly significant 20% (6-32; P = .006) reduction amongst the 2034 PAD participants whose pre-treatment measurements of LDL cholesterol were below 3.0 mmol/L (116 mg/dL), which was similar to the highly significant 25% (13-34; P < .0001) reduction seen among other high-risk individuals recruited with LDL cholesterol below 3.0 mmol/L (Fig 4). Furthermore, this proportional reduction in risk was independent of the nature of participants’ pre-existing peripheral arterial disease, with a highly significant 24% reduction (13-33; P = .0002) among the 2339 patients with prior peripheral arterial revascularizations/amputations and a similar, highly significant, 21% reduction (11-29; P < .0001) seen among the remaining 4409 patients with PAD. Effects on peripheral vascular events subdivided by prior PAD and other characteristics Overall, allocation to simvastatin was associated with a significant 16% (5-25; P = .006) proportional reduction in the rate of first peripheral vascular event following randomisation (479 [4.7%] simvastatin-allocated vs 561 [5.5%] placebo-allocated), which was not significantly influenced by baseline characteristics, including prior PAD, coronary disease, diabetes, age, or pre-treatment lipid levels (Fig 5). But, since the patients with PAD were at particularly high risk of peripheral vascular events, this relative risk reduction translated into much larger absolute reductions in participants with pre-existing PAD (20 [SE 8] per 1000) than in those without PAD (3 [SE 2] per 1000: Fig 5). The overall reduction in peripheral vascular events was due chiefly to a 20% relative reduction in non-coronary revascularizations (334 [3.3%] simvastatin vs 415 [4.0%] placebo; P = .002), reflecting significant reductions in both carotid endarterectomy or angioplasty (42 [0.4%] vs 82 [0.8%]; P = .0003) and in other non-coronary revascularization procedures (295 [2.9%] vs 344 [3.4%]; P = .04). There was no apparent effect on the incidence of aneurysms repairs or deaths (120 [1.2%] vs 113 [1.1%]; P = .7) or of amputations (95 [0.9%] vs 103 [1.0%]; P = .5). Safety Simvastatin 40 mg daily was well tolerated during the trial, with no significant effect on liver enzymes or other adverse effects. Myopathy (muscle pain and/or weakness associated with an elevation in creatine kinase >×10 ULN) is a recognized rare side-effect of all statins, but the estimated excess risk with this dose of simvastatin was only about 1 per 10,000 patients per year.17 Discussion HPS provides the first reliable evidence that cholesterol-lowering statin therapy can produce substantial reductions of around one-quarter in the risk of major vascular events (heart attacks, strokes and revascularizations) among people with PAD, even if they do not already have manifest coronary disease. These beneficial effects are largely irrespective of baseline cholesterol and independent of, and hence additional to, those of other treatments used by such patients (including anti-hypertensive therapy and various other types of cardio-protective drugs). The absolute benefits in participants with PAD were at least as great as among the other high-risk groups studied, and involved a greater absolute reduction in non-coronary revascularization procedures. Observational studies suggest that patients with overt PAD tend to be less well managed in terms of risk factor modification than patients with manifest coronary disease, despite their similar (or even higher) vascular risk, with as few as one-third of patients with PAD receiving statin therapy.20 Prior to HPS, the role of lipid lowering therapy in the PAD population was unclear. A meta-analysis of “pre-statin” trials of lipid-lowering interventions24 and a subsequent larger study of bezafibrate in men with PAD25 did not provide clear evidence of benefit, and few patients with PAD were included in other randomized statin trials. By contrast, the present analyses of HPS show that continued statin treatment prevents not just the first occurrence of major vascular events in patients with PAD but also prevents subsequent events. Hence, among the 63 PAD participants per 1000 in HPS who avoided at least one major vascular event during 5 years of allocated simvastatin treatment, 116 first or subsequent major vascular events were avoided. Due in part to this effect on both first and subsequent events, an economic analysis of HPS has shown that 40 mg daily simvastatin should generally be cost-saving for patients with PAD.26 Because of its large size and the inclusion of almost 7000 individuals with pre-existing PAD, many more participants in HPS suffered peripheral vascular events than in any other randomized trial of cholesterol-lowering therapy (in which such events were either not recorded or occurred too infrequently to allow a reliable estimation of the effect of allocated therapy). Consequently, HPS is able to demonstrate reliably that statin therapy produces a definite reduction of around one-sixth in the risk of peripheral vascular events, both among patients with pre-existing PAD and among the other high-risk individuals studied who did not have diagnosed PAD. The magnitude of the relative reduction observed in peripheral vascular events is somewhat smaller than that observed in major coronary events, strokes or all revascularizations. This smaller effect on peripheral events may be due to the play of chance, or the more insidious nature of peripheral arterial disease (in which progression from intermittent claudication to critical limb ischemia and amputation is uncommon27), or the inclusion of outcomes that are not influenced by treatment. In particular, whereas allocation to simvastatin produced a 20% reduction in the rate of non-coronary revascularization procedures, there was no apparent effect on the incidence of amputations or fatal or repaired aneurysms (although, there were too few such events to rule out favorable effects). Long-term follow-up of HPS participants is ongoing, and it remains possible that evidence of benefit on these outcomes may still emerge. Previous placebo-controlled trials and observational studies have suggested a beneficial effect of statin therapy on intermittent claudication by retarding symptom progression,28, 29, 30, 31, 32 but the development or worsening of intermittent claudication was not systematically recorded in HPS. Despite this, the results of HPS clearly demonstrate that statin therapy should be considered for all patients with intermittent claudication to reduce their very significant risk of cardiovascular mortality and major morbidity. Furthermore, these intention-to-treat results probably underestimate the benefits of taking 40 mg simvastatin daily. During HPS, the average difference in LDL cholesterol of about 1.0 mmol/L (39 mg/dL) that was observed between all those allocated simvastatin and all those allocated placebo represents only about two-thirds of the LDL cholesterol difference produced by the actual use of 40 mg simvastatin daily (due to the “drop-out” and “drop-in” rate of around one-sixth in those allocated simvastatin and placebo respectively). Similarly, the reduction of about a quarter in major vascular events in these intention-to-treat comparisons is likely to represent only about two-thirds of the risk reduction produced by actual compliance with this statin regimen. Hence, actual use of 40 mg simvastatin daily would lower LDL cholesterol by about 1.5 mmol/L (58 mg/dL) in this population and would probably reduce the rates of heart attacks, strokes, and revascularizations by about one-third and the rates of peripheral vascular events by about one-quarter. HPS clearly demonstrates the benefits of cholesterol-lowering statin therapy in patients with PAD, safely producing highly significant reductions in cardiovascular morbidity and mortality in this high-risk group. In addition, statin use reduced the incidence of peripheral vascular events in all of the high-risk groups studied. These beneficial effects are largely irrespective of baseline cholesterol levels or other features. Consequently, statin therapy should be considered routinely for all people with, or at risk of, peripheral arterial disease. Author contributions Conception and design: RB, LB, KW, SP, JA, RC Analysis and interpretation: RB, LB, KW, SP, JA, RC Data collection: RB, LB, KW Writing the article: RB, LB, KW, SP, JA, RC Critical revision of the article: RB, LB, KW, SP, JA, RC Final approval of the article: RB, LB, KW, SP, JA, RC Statistical analysis: SP, KW Obtained funding: RC, SP Overall responsibility: RC The most important acknowledgment is to the participants in the study, and to the doctors, nurses, and administrative staff in hospitals and general practices throughout the United Kingdom who assisted with its conduct. Appendix Additional material for this article may be found online at www.jvascsurg.org. MRC/BHF Heart Protection Study Collaborative Group Writing Committee–Richard Bulbulia, Louise Bowman, Karl Wallendszus, Sarah Parish, Jane Armitage, and Rory Collins. Steering Committee–R Collins (principal investigator), T Meade (chairman), P Sleight (vice-chairman), J Armitage (clinical coordinator), S Parish and R Peto (statisticians), L Youngman (laboratory director), M Buxton, D de Bono (deceased), C George, J Fuller, A Keech, A Mansfield, B Pentecost, D Simpson, C Warlow; J McNamara and L O’Toole (MRC observers). Data Monitoring Committee–R Doll (chairman; deceased), L Wilhelmsen (vice-chairman), K M Fox, C Hill, P Sandercock. Collaborators–listed in reference 17. References 1. 1Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985;71:510–515. MEDLINE 2. 2Meijer WT, Hoes AW, Rutgers D, Bots ML, Hofman A, Grobbee DE. Peripheral arterial disease in the elderly: The Rotterdam Study. Arterioscler Thromb Vasc Biol. 1998;18:185–192. MEDLINE 3. 3Fowkes FG, Housley E, Cawood EH, Macintyre CC, Ruckley CV, Prescott RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1991;20:384–392. MEDLINE 4. 4Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–386. MEDLINE 5. 5Jacobs D, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, et al. Report of the Conference on Low Blood Cholesterol: Mortality Associations. Circulation. 1992;86:1046–1060. MEDLINE 6. 6Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434–444. MEDLINE 7. 7Chen J, Campbell TC, Li J, Peto R. Diet, lifestyle and mortality in China. Oxford: Oxford University Press; 1990;. 8. 8Szatrowski TP, Peterson AV, Shimizu Y, Prentice RL, Mason MW, Fukunaga Y, et al. 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 Correspondence to: Heart Protection Study, Clinical Trial Service Unit and Epidemiological Studies Unit, Richard Doll Building, University of Oxford, Old Road Campus, Roosevelt Dr, Oxford OX3 7LF, UK.
The study was funded by the UK Medical Research Council (MRC), the British Heart Foundation (BHF), Merck & Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of the vitamins). Competition of interest: The Clinical Trial Service Unit has a staff policy of not accepting honoraria or other payments from the pharmaceutical industry, except for the reimbursement of costs to participate in scientific meetings. Members of the writing committee have, therefore, only had such costs reimbursed. CME article PII: S0741-5214(07)00003-1 doi:10.1016/j.jvs.2006.12.054 © 2007 The Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. | |
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