Anglo-Scandinavian Cardiac Outcomes Trial -- Lipid Lowering Arm (ASCOT-LLA): Int

Antihypertensive and Lipid-Lowering Therapy

Disclosures

Linda Brookes, MSc

Presenter: Peter S. Sever, MB BChir, PhD (Imperial College London, United
Kingdom)
Unblinding of the blood pressure (BP) treatment assignments in the original lipid-lowering arm of the Ang
Scandinavian Cardiac Outcomes Trial (ASCOT) has revealed that the benefits of atorvastatin on corona
endpoints were greater in the subjects assigned to an amlodipine-based treatment strategy than those
assigned to atenolol-based treatment.[1] This new result showing an apparent benefit to adding a statin t
dihydropyridine calcium channel blocker (CCB) for prevention of future coronary heart disease (CHD)
events has important implications for optimal treatment strategies for hypertensive patients, the ASCO
investigators believe.

ASCOT Methods and Results

The primary objective of each of the 2 arms of ASCOT was to assess the differential effect on risk of
nonfatal myocardial infarction (MI) and fatal CHD of 2 different treatment strategies assessed in a 2 X
factorial design[2]:

1. A traditional antihypertensive regimen (beta-blocker ± diuretic) vs a contemporary regimen (CC

angiotensin converting enzyme [ACE] inhibitor) in the trial's BP-lowering arm (ASCOT BPLA

2. A statin vs a placebo in those patients with total cholesterol ≤ 6.5 mmol/L (250 mg/dL) in the tri
lipid-lowering arm (ASCOT LLA).

A total of 19,257 hypertensive patients were randomized to 1 of the 2 BP-lowering strategies, and 10,30
these patients were further randomized to atorvastatin 10 mg or placebo.

ASCOT-LLA was stopped early in 2002, and the results were published in 2003.[3] The trial indicated th
active treatment with atorvastatin resulted in significant reductions in the primary endpoint (nonfatal MI a
fatal CHD) of 36%, and in secondary endpoints of all coronary events (29%), fatal and nonfatal stroke
(27%), and all cardiovascular events and procedures (21%). However, at the time that this clear advanta
of statin therapy was demonstrated, the antihypertensive strategy (CCB or beta-blocker based) the patie
were assigned to was still blinded.

The results of ASCOT-BPLA, which was also terminated early, with results published in September 200
did not show a statistically significant reduction in the primary endpoint. The ASCOT investigators belie
this was due to the lower number of events achieved as a consequence of the early termination of this a
of the study. Significant reductions were seen in a number of secondary endpoints.

However, with the unblinding of the antihypertensive assignments, it was possible to go back and re-
examine the ASCOT-LLA results. These new data thus come from a prespecified analysis of the potent
interaction between lipid-lowering therapy and antihypertensive treatment on the primary endpoint of
ASCOT-LLA, total cardiovascular events and procedures, and stroke.

Interaction Between Lipid-Lowering and Blood

Pressure-Lowering Treatments
Following unblinding of the BP treatment arms in ASCOT-LLA, it was seen that there was a much grea
risk reduction induced by atorvastatin compared with placebo in the primary endpoint among subjects
originally assigned to the amlodipine-based treatment compared with those assigned to the atenolol-bas
treatment. The primary endpoint was significantly reduced by 53% in the amlodipine/atorvastatin grou
 compared with amlodipine/placebo, and compared with a nonsignificant reduction of 16% in the group
assigned to atenolol/atorvastatin vs atenolol/placebo (Table 1). The benefits of atorvastatin compared w
placebo were also greater for several other endpoints in subjects assigned to amlodipine-based treatme
compared with atenolol-based treatment. Total cardiovascular procedures were reduced by 27% and 15
respectively, and fatal and nonfatal stroke incidences were reduced by 31% and 24%, respectively.

Table 1. ASCOT-LLA: Risk Reduction in Blood Pressure Treatment Arms

Amlodipine Atenolol
Endpoint HR 95% CI P HR 95% CI P
Nonfatal MI and fatal CHD 0.47 0.32-0.69 < .001 0.84 0.60-1.17 .30
Total cardiovascular events and procedures 0.73 0.60-0.88 .001 0.85 0.71-1.02 .08
Fatal and nonfatal stroke 0.69 0.4-1.06 .09 0.76 0.63-1.08 .013>
CHD = coronary heart disease; CI = confidence interval; HR = hazard ratio; MI = myocardial infarction
A formal statistical test for interaction between lipid-lowering and BP-lowering treatment was of borderli
significance for the primary endpoint of nonfatal MI plus fatal CHD (P = .025, with statistical significanc
defined as P ≤ .01), but not for total cardiovascular events and procedures (P = .25) or for stroke (P = .7
Interaction for addition of revascularization to the primary endpoint and on-treatment nonfatal MI plus fa
CHD were each of borderline statistical significance (both P = .043) (Table 2).

Table 2. ASCOT-LLA: Test for Interaction

Endpoint P Value for Interaction

Nonfatal MI and fatal CHD .025
Total cardiovascular events and procedures .25
Fatal and nonfatal stroke .73
Revascularization + nonfatal MI and fatal CHD .043
On-treatment nonfatal MI and CHD .043
CHD = coronary heart disease; MI = myocardial infarction
A posthoc analysis of the primary endpoint at various time points showed that significant benefit of
atorvastatin was already apparent at 30 days, and a highly significant risk reduction in the primary endpo
with atorvastatin was seen from 90 days of observation through to the end of the trial. However, the ea
benefits of atorvastatin were only seen in the subjects on amlodipine therapy, and no significant benefits
atorvastatin were apparent at any time point in the subjects on atenolol-based therapy.

Possible Mechanism of Interaction

The ASCOT investigators believe that while these observations could be a chance finding, there is
plausible biological explanation for a synergistic effect of atorvastatin- and amlodipine-based treatment
acute coronary events, on the basis of experimental studies. Their hypothesis is based on electrochemi
bonding of atorvastatin and amlodipine in the lipid bilayer of the vascular smooth muscle cell membrane
previously proposed by R. Preston Mason, PhD (Brigham and Women's Hospital, Boston, Massachuset
Vascular smooth muscle cells play an integral role in the evolution of the atherosclerotic plaque. Large
under the influence of cytokine release from macrophages, smooth muscle cells migrate, proliferate, an
de-differentiate via a calcium ion-dependent process into a "synthetic" cell phenotype. These syntheti
proliferating cells form the fibrous cap of the plaque. As these synthetic cells continue to proliferate, the
release matrix metalloproteinases (MMPs) in addition to the MMPs that are released from lipid-laden
macrophages; these MMPs in turn lead to cell death (apoptosis) and destruction of the intercellular mat
in the fibrous cap, eventually leading to rupture of the plaque.

As the contractile smooth muscle cells transform to the de-differentiated synthetic phenotype, they lose
 functionality of their L-type voltage-operated calcium channels. With the loss of the L-type calcium chann
CCBs would no longer be effective. However, statins, acting via the mevalonate pathway, arrest growth
these synthetic cells, leading to re-expression of functioning L-type voltage operating calcium channels a
restoration of responsiveness to dihydropyridine CCBs. Thus, there is a transformation of the syntheti
cells back to a more stable, differentiated phenotype, and these more highly differentiated smooth musc
cells are likely to enhance the stability of the plaque, leading to fewer coronary events.

Implications for Therapy in Hypertension

Prof. Sever believes that in the context of hypertension, it is important to determine the level of risk tha
warrants introduction of statins as concomitant therapy: "Clearly, from the observations from ASCOT an
other studies, it is highly likely that the statin benefits will lower levels of absolute risk and I think it is
important that more trials are done. I think that in the context of hypertension, you really do have to ask
question, why is my patient not on a statin? The evidence is fairly convincing that they will almost certai
benefit."

References
1. Sever PS, Dahlof B, Poulter NP, Wedel H. Anglo-Scandinavian Cardiac Outcomes Trial: Lipi
Lowering Arm (ASCOT LLA) revisited: interaction of antihypertensive and lipid lowering therap
Circulation. 2005;112(17 Suppl):II-134. Abstract 730.
2. Sever PS, Dahlof B, Poulter NR, et al; ASCOT investigators. Rationale, design, methods and
baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. J
Hypertens. 2001;19:1139-1147.
3. Sever PS, Dahlof B, Poulter NR, Wedel H, et al; ASCOT investigators. Prevention of coronary a
stroke events with atorvastatin in hypertensive patients who have average or lower-than-avera
cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial -- Lipid Lowerin
Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158.
4. Dahlof B, Sever PS, Poulter NR, for the ASCOT investigators. Prevention of cardiovascular eve
with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolo
adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blo
Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet.
2005;366:895-906.

Copyright © 2005 Medscape.

Title: The Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm: Extended Observations 2 Years After Trial Closure
Topic: Prevention/Vascular
Date Posted: 2/7/2008
Author(s): Sever PS, Poulter NR, Dahlof B, et al., on behalf of the ASCOT Investigators.
Citation: Eur Heart J. 2008;Jan 5:[Epub ahead of print].
Clinical Trial: No
Potential synergy between lipid-lowering and blood-pressure-lowering in the
Anglo-Scandinavian Cardiac Outcomes Trial
Peter Sever, Björn Dahlöf, Neil Poulter, Hans Wedel, Gareth Beevers, Mark
Caulfield, Rory Collins, Sverre Kjeldsen, Arni Kristinsson, Gordon McInnes, Jesper
Mehlsen, Markku Nieminem, Eoin O'Brien, Jan Östergren on behalf of the ASCOT
Steering Committee Members

Clinical Pharmacology and Therapeutics, Imperial College London, International Centre for Circulatory Health, 59 North Wharf
Road, London W2 1PG, UK

Received 30 May 2006; revised 5 October 2006; accepted 7 November 2006; online publish-ahead-of-print
4 December 2006.

Corresponding author. Tel: +44 0 207 594 1100; fax:+44 0 207 594 1145. E-mail address: p.sever@imperial.ac.uk

Abstract

Aims A prespecified objective of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was to assess
whether any synergistic effects were apparent between the lipid-lowering and blood-pressure-lowering
regimens in preventing cardiovascular events.

Methods and results A total of 19 257 hypertensive subjects were randomized to an amlodipine-based
regimen or an atenolol-based regimen. Of these, 10,305 subjects with total cholesterol 6.5 mmol/L were
further randomized to atorvastatin 10mg daily or placebo. In this analysis, the effects of atorvastatin were
compared with placebo on coronary heart disease (CHD), cardiovascular and stroke events in those
assigned amlodipine-based and atenolol-based regimens. In the ASCOT lipid-lowering arm (LLA), overall,
atorvastatin reduced the relative risk of the primary endpoint of non-fatal myocardial infarction and fatal
CHD events by 36% (HR 0.64, CI 0.50-0.83, P=0.0005), total cardiovascular events by 21% (HR 0.79, CI
0.69–0.90, P=0.0005), and stroke by 27% (HR 0.73, CI 0.56–0.96, P=0.024).

However, atorvastatin reduced the relative risk of CHD events by 53% (HR 0.47, CI 0.32–0.69, P<0.0001)
among those allocated the amlodipine-based regimen, and by 16% (HR 0.84, CI 0.60–1.17, p: n.s.) among
those allocated the atenolol-based regimen (P=0.025 for heterogeneity). There were no significant
differences between the effects of atorvastatin on total cardiovascular events or strokes among those
assigned amlodipine (HR 0.73, CI 0.60–0.88, P<0.005 and HR 0.69, CI 0.45–1.06, P: n.s., respectively) or
atenolol (HR 0.85, CI 0.71–1.02, P: n.s and HR 0.76, CI 0.53–1.08, P: n.s, respectively). Differences in
blood pressure and lipid parameters (placebo corrected) between the two antihypertensive treatment limbs
could not account for the differences observed in CHD outcome.

Conclusion These findings of an apparent interaction between atorvastatin and an amlodipine-based

regimen in the prevention of CHD events are of borderline significance, and hence generate an hypothesis
that merits independent evaluation in other trials.