The European Society of Cardiology
Implications of recent end-point trials on future management of hypertension and dyslipidaemia
Sahlgrenska University Hospital/Östra, Gothenburg University, Gothenburg, Sweden
* Correspondence: B. Dahlöf, Sahlgrenska University Hospital/Östra, Gothenburg University, Gothenburg, Sweden. Tel.: +46 31 343 5305; fax: +46 31842217 (E-mail: bjorn.dahlof{at}scri.se).
Abstract
A significant proportion of patients with hypertension are likely to have additional cardiovascular (CV) risk factors, such as hypercholesterolaemia. Several trials have demonstrated that lipid lowering can provide significant benefits in terms of reduced risk of CV mortality and morbidity. Trials such as the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial have shown regression of atherosclerosis after aggressive lipid-lowering treatment with statins. The Heart Protection Study (HPS) also demonstrated a significant reduction in the incidence of major vascular events in high-risk patients, irrespective of baseline cholesterol levels, after treatment with a statin. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is of particular significance because it investigated the impact of combining the effects of antihypertensive therapy with a statin. ASCOT was a multi-centre, 2x2 factorial design, randomized trial comparing two blood pressure (BP)-lowering regimens in the antihypertensive arm, and double-blind atorvastatin (10 mg) versus placebo in a separate lipid-lowering arm (LLA). The objective of the LLA was to compare the effects of low-dose atorvastatin versus placebo for the combined end-point of nonfatal myocardial infarction and fatal coronary heart disease (CHD) in hypertensive patients with normal to mildly elevated cholesterol levels (total cholesterol 
6.5 mmoll–1; 250 mgdl–1). The ASCOT–LLA represents the first study to assess the benefits of lipid lowering in the primary prevention of CHD in well-controlled hypertensive patients who are not conventionally deemed dyslipidaemic. Secondary end-points included all-cause mortality, fatal and nonfatal stroke and total coronary events. The ASCOT–LLA, which had a 5-year planned follow-up, was terminated prematurely by the Data Safety Monitoring Board, after a median follow-up of 3.3 years due to a highly significant reduction in the primary end-point of 36% compared with placebo (P=0.0005). ASCOT and other end-point studies suggest that controlling both BP and dyslipidaemia may have a synergistic benefit on CV mortality and morbidity. Future treatment strategies should therefore be aimed at addressing global CV risk in each patient and not just individual risk factors.
Keywords Hypercholesterolaemia; Lipid lowering; Statins; Hypertension
Introduction
More than 200 million people worldwide are at high risk of having a cardiovascular (CV) event. The most important cause of mortality worldwide is hypertension, and the distribution of other global risk factors demonstrates that smoking and hypercholesterolaemia represent the second and third greatest risks to mortality, respectively.1 Although the treatment of hypertension has been extremely well investigated in numerous clinical trials, there are still problems with blood pressure (BP) control because of issues such as poor medication and tolerability, suboptimal compliance and a failure to recognize the importance of goal attainment. In Sweden, for example, the MONItor CArdiovascular trends (MONICA) survey demonstrated that many hypertensive patients are either undiagnosed, or diagnosed but treated inadequately – of those patients who are treated, only one-third are controlled. Untreated and poorly controlled hypertension was associated with a 4–6 times higher risk for stroke, and of the 129 cases of stroke detected in MONICA, only one patient had treated and controlled hypertension.2
Evidence of lipid-lowering benefit in hypertension
It is now recognized that patients with hypertension are highly likely to have additional CV risk factors, with less than 20% of hypertension cases occurring in isolation.3 The Multiple Risk Factor Intervention Trial (MRFIT) clearly demonstrated the additive effect of cholesterol and systolic blood pressure (SBP) on the risk of coronary heart disease (CHD) death (Fig. 1). MRFIT also showed that a modest elevation in hypertension and dyslipidaemia could convey as much risk of death as the severe elevation of one risk factor.4
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Over the last decade, several major landmark clinical trials have clearly shown that lipid lowering with statins results in significant reductions in the risk of CV mortality and morbidity.5–9 More recently, results from the Heart Protection Study (HPS)10 demonstrated a significant reduction in the incidence of major vascular events in high-risk patients treated with simvastatin. The HPS was among one of the first trials to recognize that lipid lowering could reduce the risk of major vascular events regardless of baseline cholesterol levels. Patients with cholesterol levels below 100 mgdl–1 (2.5 mmoll –1), between 100 and 130 mgdl–1 or ⩾130 mgdl–1 (⩾3.36 mmoll–1) achieved the same benefit after treatment with 40 mg of simvastatin. Furthermore, studies such as the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial11 have demonstrated a reduction in carotid intima-media thickness following aggressive lipid lowering with atorvastatin versus simvastatin in patients with familial hypercholesterolaemia.
The benefits of lipid lowering have also been investigated in the two largest CV risk-reduction trials to date – the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT)12,13 and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).14,15 The ASCOT and ALLHAT studies are of particular relevance to the benefits associated with multiple therapy because they included both an antihypertensive and a lipid-lowering arm (LLA). The ALLHAT-LLA13 failed to demonstrate a benefit for the primary end-point when pravastatin was compared with usual care. This was attributed to the fact that a significant difference in total cholesterol and low-density lipoprotein (LDL)-cholesterol could not be maintained between the two groups during the course of the study. Thus, the treatment difference in total cholesterol in ASCOT after 3 years was 1.1 mmoll–1 (42 mgdl–1) in contrast to a difference of only 0.6 mmoll–1 (23 mgdl–1) in ALLHAT. This difference was mainly due to the fact that in the ASCOT-LLA there was better patient compliance in the atorvastatin group, and less crossover to statin treatment in the placebo group than in ALLHAT.
ASCOT and its implications
Rationale
The impetus to initiate ASCOT lay in the increased incidence of CHD, which still represents a major unresolved problem. One of the reasons for the continuing high prevalence of CHD can be related to the interaction between dyslipidaemia and hypertension. Before ASCOT, no trial had attempted to address the benefits of lipid lowering in the primary prevention of CHD and other CV complications in treated hypertensive patients who were not conventionally deemed dyslipidaemic. (Patients with a previous history of CHD were excluded.)
Design
The study fulfilled all the criteria expected of a large, robust trial. The ASCOT–LLA was double blind and the BP-lowering arm used a prospective randomized open blind end-points (PROBE) design. The LLA consisted of a randomized comparison between atorvastatin and placebo in a 2x2 factorial design, in patients with cholesterol levels that were not deemed to be dyslipidaemic. The primary objective of the LLA was to compare the preventative effects of using atorvastatin (10 mg) versus placebo over 5 years on the combined outcome of nonfatal myocardial infarction (MI) and fatal CHD in well-controlled hypertensive patients with total cholesterol levels below 6.5 mmoll–1 (250 mgdl–1).
Patient characteristics
Baseline characteristics reflected mild-to-moderate-risk patients: mean age 63 years, predominantly men, hypertensive (mean SBP 164 mmHg; mean diastolic blood pressure [DBP] 95 mmHg), mean total cholesterol 5.5 mmoll–1 (213 mgdl–1), mean LDL 3.4 mmoll–1 (132 mgdl–1), and increased triglycerides and low high-density lipoprotein (HDL). Other risk factors included microalbuminuria, smoking and type 2 diabetes. It is also important to emphasize that ASCOT was a primary prevention trial, since few patients had previous cerebrovascular disease and none had previous CHD.
Results
No difference was detected in BP control between the two treatment arms as a result of the factorial design and randomized treatment. After treatment in the BP-lowering arm, patients achieved good mean BP control (138/80 mmHg). It was possible to maintain the majority of patients in the LLA on either atorvastatin or placebo for the duration of the study (after 3 years only 9% in the placebo arm received statin treatment, whereas 87% in the statin arm were maintained on atorvastatin). As a consequence, the difference in cholesterol between the arms was substantial (Fig. 2): total cholesterol (1.1 mmoll–1; 43 mgdl–1), LDL-cholesterol (1.0 mmoll–1; 38 mgdl–1) and triglycerides (0.2 mmoll–1; 18 mgdl–1) all demonstrated differences in favour of atorvastatin. No difference was apparent for HDL-cholesterol. These differences in lipid levels between the two treatment arms are likely to explain why significant differences were observed for the primary and secondary outcomes in ASCOT.
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The results for ASCOT–LLA15 are even more clinically relevant given that the study was terminated prematurely after
3 years. The primary end-point of fatal CHD and nonfatal MI was significantly lower by 36% (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.50–0.83], P=0.0005) in the atorvastatin group compared with the placebo group after 3.3 years follow-up. This benefit began to emerge during the first year. Fig. 3 illustrates the very early separation of the cumulative incidence of the primary end-point, a trend that continued to widen throughout follow-up. A 21% reduction in total CV events including revascularization procedures (HR=0.79 [95% CI 0.69–0.90], P=0.0005), a 29% reduction in total coronary events (HR=0.71 [95% CI 0.59–0.86], P=0.0005), and a 27% reduction in fatal and nonfatal stroke (HR=0.73 [95% CI 0.56–0.96], P=0.0236) was also seen. Early separation was observed between the atorvastatin and placebo arms for each of these secondary end-points.
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Subgroup analyses of total CV events and procedures confirmed a similar benefit with atorvastatin, with no significant heterogeneity observed across each subgroup investigated. Post-hoc analysis of the benefit across the cholesterol range confirmed the HPS findings that lipid lowering is equally beneficial regardless of the starting cholesterol level10 – in ASCOT–LLA, atorvastatin provided a significant reduction of 35% and 37% in the primary end-point for patients with baseline total cholesterol
5.6 mmoll–1 (217 mgdl–1) and >5.6 mmoll–1 (>217 mgdl–1), respectively. In terms of safety, the incidences of fatal cancer and non-CV death were similar between the atorvastatin and placebo groups. Furthermore, there was no difference in the number of serious adverse events or liver enzyme abnormalities between treatment groups.
Discussion
The ASCOT–LLA demonstrated that, in well-controlled hypertensive patients at a modest risk of CHD with normal to moderate elevated cholesterol levels, atorvastatin (10 mg) significantly reduced nonfatal MI and fatal CHD, stroke and total CV events and procedures after only 3.3 years of treatment. The reductions in total cholesterol and LDL-cholesterol were greater, and CV benefits demonstrated earlier than in other landmark statin trials, such as the West Of Scotland COronary Prevention Study (WOSCOPS)7 and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).8 It was also documented that the risk reduction in CHD was unrelated to the cholesterol baseline levels, and that the benefits occurred in the absence of any serious adverse events.
Approximately 5 million people die from stroke every year and more than 15 million are left disabled, which has a huge impact on global health resources. It is recognized that treatment with a statin can help reduce the risk of stroke,5 although the precise mechanism responsible has yet to be elucidated. Several proposed mechanisms are related to the antithrombotic, anti-inflammatory, endothelial-protective and antioxidant properties of statins.16 The findings from ASCOT–LLA have important ramifications for the treatment of stroke because the benefit associated with atorvastatin was observed in a population of well-controlled hypertensive patients.
In terms of numbers needed to treat (NNT), it is evident that the values achieved for the reduction of total coronary events in ASCOT (NNT=45) are approximately the same as the NNT for other lipid-lowering trials, e.g. WOSCOPS (NNT=44), AFCAPS (NNT=49) and HPS (NNT=54), and the NNT for all CV events will obviously be lower.
Conclusion
In conclusion, the findings from ASCOT suggest that controlling both BP and dyslipidaemia could have a synergistic benefit on CV mortality and morbidity. ASCOT–LLA supports epidemiological evidence that there is no detectable cholesterol threshold for risk, and reinforces a more aggressive treatment approach to lower cholesterol levels among patients with hypertension. Furthermore, ASCOT–LLA reinforces the concept that treatment strategies should be based on overall CV risk rather than on individual risk factors. Based on this study, and the findings from other landmark clinical trials,5–10 statins should be advocated for the majority of patients with hypertension and increased CV risk. This recommendation is reflected in the current guidelines from the European Society of Hypertension and European Society of Cardiology (ESH–ESC).17 In view of ASCOT and other trial data, these guidelines suggest that all patients aged up to 80 years with a total cholesterol >3.5 mmoll–1 (>135 mgdl–1), who have an estimated 10-year CV risk of 
20%, should be treated with a statin. Applying the recommendations from these and similar guidelines into clinical practice will optimize the management of hypertension and dyslipidaemia and will, ultimately, reduce the global risk of CV disease.
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