Ezetimibe with simvastatin, tablets, 10 mg - 20 mg, Vytorin®, March 2009
Public summary document for Ezetimibe with simvastatin, tablets, 10 mg - 20 mg, Vytorin®, March 2009
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Public Summary Document
Product: Ezetimibe with simvastatin, tablets, 10
mg - 20 mg, Vytorin®
Sponsor: Merck Sharp & Dohme (Australia) Pty
Ltd (and Schering – Plough Pty Ltd)
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought to list a new strength of ezetimibe with
simvastatin and to lower the threshold dose to a daily dose of 20
mg or greater of a statin instead of the current daily dose 40 mg
or greater.
2. Background
The March 2005 PBAC meeting recommended an authority required
listing of ezetimibe with simvastatin (10/40 mg and 10/80 mg) on a
cost-minimisation basis compared to the sum of the corresponding
strengths of the individual components for use in patients with CHD
or diabetes. Vytorin was first PBS-listed on 1 February 2006. The
listing was expanded to other high risk patient groups at the PBAC
meetings in November 2005 and November 2006.
The November 2006 meeting also considered an application to list a
new strength of ezetimibe with simvastatin (10/10 mg). This was
rejected on the grounds of unclear clinical need, and unnecessary
proliferation of dosage forms.
This fixed strength of the combination of ezetimibe and simvastatin
had not previously been considered by the PBAC.
3. Registration Status
Ezetimibe with simvastatin 10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg were TGA registered on 07 January 2005 for the following:
- Primary hypercholesterolemia - as adjunctive therapy to diet in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia where use of a combination product is appropriate:
- Patients not appropriately controlled with a statin or ezetimibe alone.
- Patients already treated with a statin and ezetimibe.
- Homozygous Familial Hypercholesterolemia (HoFH). Patients may also receive adjunctive treatments (e.g., LDL apheresis).
4. Listing Requested and PBAC’s View
Authority Required (Streamlined)
Changes to the current listing are highlighted onBOLD
Treatment, in conjunction with dietary therapy and exercise, in patients whose cholesterol
levels are inadequately controlled with an HMG CoA reductase inhibitor (statin) and
who have:
(a) coronary heart disease; or
(b) diabetes mellitus; or
(c) peripheral vascular disease; or
(d) heterozygous familial hypercholesterolaemia; or
(e) cerebrovascular disease which has become symptomatic; or
(f) family history of coronary heart disease; or
(g) hypertension.
Inadequate control with a statin is defined as follows:
(1) where the patient falls into a category for which the General Statement for Lipid-Lowering
Drugs includes an initial cholesterol threshold for PBS-subsidy, a cholesterol level
in excess of that threshold after at least 3 months of treatment at a daily dose of
20 mg or greater of a statin, in conjunction with dietary therapy and exercise. The dose
and duration of statin treatment and the cholesterol level which shows inadequate
control must be documented in the patient's medical records when the ezetimibe component
is initiated. The cholesterol level which shows inadequate control must be no more
than 2 months old when the ezetimibe component is initiated; or
(2) where the patient falls into a category for which the General Statement for Lipid-Lowering
Drugs allows PBS-subsidised treatment with a statin at any cholesterol level, a cholesterol
level in excess of 4 mmol per L after at least 3 months of treatment at a daily dose
of 20 mg or greater of a statin, in conjunction with dietary therapy and exercise. The dose
and duration of statin treatment and the cholesterol level which shows inadequate
control must be documented in the patient's medical records when the ezetimibe component
is initiated. The cholesterol level which shows inadequate control must be no more
than 2 months old when the ezetimibe component is initiated.
Patients with homozygous familial hypercholesterolaemia who are eligible for PBS-subsidised
lipid-lowering medication (according to the criteria set out in the General Statement
for Lipid-Lowering Drugs).
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Vytorin 10/20 mg would provide an alternative therapy in patients
whose cholesterol is not controlled on 20 mg of a statin or
greater.
6. Comparator
The submission nominated simvastatin 40 mg, atorvastatin 20 mg and
40 mg and rosuvastatin 20 mg as the main comparators i.e.,
up-titration of statin dose from statin 20 mg or switching to a
more potent statin which was considered appropriate by the
PBAC.
7. Clinical Trials
The submission presented five randomised trials comparing Vytorin
10/20 or ezetimibe 10 mg/simvastatin 20 mg with simvastatin 40 mg
and atorvastatin 20 mg in patients with hypercholesterolemia where
patients were being treated in the second-line setting (i.e.,
randomised to treatment after a run-in period on statin 20 mg).
Three of the five trials conducted in the second-line setting
randomised patients to ezetimibe/simvastatin or up-titration of
statin following inadequate control on a stable statin dose and the
remaining two trials randomised patients to ezetimibe/simvastatin
or up-titration of statin regardless of lipid control.
The submission also presented four randomised trials comparing
Vytorin 10/20 or ezetimibe 10 mg/simvastatin 20 mg with
atorvastatin 40 mg and rosuvastatin 20 mg in patients with
hypercholesterolemia where patients were treated in the first-line
setting i.e., randomised to treatment after a run-in period on
placebo.
The studies published at the time of the submission, are as
follows:
| Trial/First author | Protocol title | Publication citation |
| Trials of EZ10/20 as versus relevant comparator(s) where treatment was received as 2nd Line therapy | ||
| Barrios et al | Lipid-altering efficacy of switching from atorvastatin 10 mg/day to ezetimibe/simvastatin 10/20 mg/day compared to doubling the dose of atorvastatin in hypercholesterolaemic patients with atherosclerosis or coronary heart disease. | Int J Clin Pract 2005; 59:1377-86. |
| EASEGO (Roeters et al) | The efficacy of statin monotherapy up titration versus switching to ezetimibe/simvastatin: | Curr Med Res Opin 2008; 24:685-94. |
| Protocol 700 | ||
| Bobs et al | Co-administration of ezetimibe with simvastatin. | J Am Coll Cardiol 2003; 41(6, Suppl. A): 227A-227A. |
| Constance et al | Efficacy of ezetimibe/simvastatin 10/20 and 10/40 mg compared with atorvastatin 20 mg in patients with type 2 diabetes mellitus. | Diabetes Obes Metab 2007; 9:575-84. |
| Protocol 021 | ||
| Gaudiani et al | Efficacy and safety of ezetimibe co-administered with simvastatin in thiazolidinedione-treated type 2 diabetic patients. | Diabetes, Obesity and Metabolism. 7(1): 88-97, 2005. |
| Gaudiani et al | Efficacy and safety of ezetimibe co-administered with simvastatin versus simvastatin alone in thiazolidinedione-treated type 2 diabetes mellitus. | Journal of the American College of Cardiology 43(5, Suppl. A): 479A-479A (#1084-169) March 2004 (in Soc. Proc.). |
| Trial/First author | Protocol title | Publication citation |
| Trials of EZ10/20 as versus relevant comparator(s) where treatment received as 1st Line therapy for where a second line comparison was not available | ||
| Protocol 051 (VYVA study) | ||
| Ballantyne et al | Attainment of optimal National Cholesterol Education Program Adult treatment panel III treatment goals in high risk patients: dose comparison of VYTORIN (ezetimibe/simvastatin) and atorvastatin. | Journal of the American College of Cardiology, 45 (3, Suppl.A) 423A-423A, 2005. |
| Ballantyne et al | Dose comparison study of the combination of ezetimibe and simvastatin (VYTORIN) versus atorvastatin in patients with hypercholesterolemia: the VYTORIN versus Atorvastatin (VYVA) study. | American Heart Journal 149(3): 464-73, 2005. |
| Ballantyne et al | Evaluation of the safety and efficacy of the ezetimibe/simvastatin combination tablet versus atorvastatin in patients with hypercholesterolemia. | XV International Symposium on Drugs Affecting Lipid Metabolism, 24-27 October 2004, Venice Italy, Abstract p124. |
| Abate et al | Ezetimibe/simvastatin versus atorvastatin for patients who have diabetes mellitus and hypercholesterolemia. | Diabetologia 48(Suppl. 1) A392-A393 (#1087) August 2005. |
| Ballantyne et al | Ezetimibe/simvastatin versus atorvastatin for patients who have diabetes mellitus and hypercholesterolemia. | Diabetes 54 (Suppl. 1): A235-A235 (#962-P) June 2005. |
| Protocol 077 (VYTAL) | ||
| Goldberg et al | Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: The VYTAL study. | Mayo Clin Proc 2006;81:1579-88. |
| Guyton et al | Lipoprotein and apolipoprotein ratios in the VYTAL trial of ezetimibe/simvastatin compared with atorvastatin in type 2 diabetes. J Clin Lipidology 2008;2:19-24. | J Clin Lipidology 2008;2:19-24. |
| Weinstock et al | Effect of ezetimibe/simvastatin vs atorvastatin on lowering levels of LDL-C and non-HDL-C, ApoB, and hs-CRP in patients with type 2 diabetes. | J Clin Lipidology 2008;2:25-35. |
| COMPELL (McKenney et al) | Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). | Atherosclerosis 2007;192:432-7. |
| Protocol 058 | ||
| Catapano et al | Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients. | Curr Med Res Opin 2006; 22:2041-53. |
| Abate et al | LDL-C lowering efficacy of the ezetimibe/simvastatin single tablet compared with atorvastatin or rosuvastatin in elderly patients with hypercholesterolemia. | J. Am. Geriatric Society 54(4, Suppl.):S163-S163 (#D22) 2006. |
8. Results of Trials
The outcome from the randomised second-line trials that was used in
the modelled economic evaluation was the percentage mean change in
Total Cholesterol:High Density Lipoprotein-C (TC:HDL-C) ratios. The
results of the meta-analyses of the second-line randomised trials
are presented below:
Results of mean change in TC:HDL-C ratio from baseline to
end point changes across the direct randomised trials (second-line
setting)
| Trial ID | V10/20 or E10/S20 | S40 or A20 | End point (weeks) | WMD (95% CI) | ||
| n/N (%) | Mean (SD) | n/N (%) | Mean (SD) | |||
| Second-line setting: Patients randomised to Vytorin 10/20 or up-titration of statin following inadequate control on a stable statin dose | ||||||
| Barrios (V10/20 v A20) | 215/221 (97.3) | -20.90 (14.66) | 207/214 (96.7) | -11.70 (14.39) | 6 | -9.20 (-11.97, -6.43) |
| EASEGO (V10/20 v A20 or S40) | 157/178 (88.2) | -13.50 (18.68) | 174/189 (92.1) | -6.10 (17.87) | 12 | -7.40 (-11.35, -3.45) |
| Pooled result (inadequate control) | Chi-square for heterogeneity: P=0.46 I 2 statistic with 95% uncertainty interval=0% | -8.61 (-10.87, -6.34) | ||||
| Second-line setting: Patients randomised to Vytorin 10/20 or up-titration of statin following run-in on a stable statin dose (not necessarily inadequately controlled) | ||||||
| Constance (E10/S20 v A20) | 219/220 (99.5) | -15.31 (19.82) | 218/219 (99.5) | -5.90 (19.81) | 6 | -9.41 (-13.13, -5.69) |
| Protocol 021 (E10/S20 v S40) | 103/104 (99.0) | -13.40 (22.27) | 107/110 (97.3) | 0.10 (17.42) | 24 | -13.50 (-18.92, -8.08) |
| Pooled result (control not determined) | Chi-square for heterogeneity: P=0.19 I 2 statistic with 95% uncertainty interval=42.5% | -10.96 (-14.85, -7.07) | ||||
| Pooled result (all trials) | Chi-square for heterogeneity: P=0.36 I 2 statistic with 95% uncertainty interval=6.0% | -9.37 (-11.27, -7.47) | ||||
V10/20=Vytorin 10/20, S40=simvastatin 40 mg, A20=atorvastatin 20
mg,
E10/S20=ezetimibe 10 mg/simvastatin 20 mg, SD=standard deviation,
WMD=weighted mean difference
The results of the meta-analysis of the first-line randomised
trials for mean Low Density Lipoprotein-C (LDL-C) percentage change
and TC:HDL-C ratios are shown below:
Results of mean LDL-C percentage change from baseline to
end point changes across the direct randomised trials (first-line
setting)
| Trial ID (comparison) | V10/20 or E10/S20 | A40 or R20 | End Point (weeks) | WMD (95% CI) | ||
| n/N (%) | Mean (SD) | n/N (%) | Mean (SD) | |||
| Protocol 051 (V10/20 v A40) | 233/238 (97.9) | -50.60 (14.02) | 232/237 (97.9) | -48.30 (14.77) | 6 | -2.30 (-4.92, 0.32) |
| Protocol 077 (V10/20 v A40) | 238/247 (96.3) | -53.60 (14.17) | 241/254 (98.4) | -50.90 (14.26) | 6 | -2.70 (-5.25, -0.15) |
| Pooled result | Chi-square for heterogeneity: P=0.83 I 2 statistic with 95% uncertainty interval=0% | -2.51 (-4.33, -0.68) | ||||
| COMPELL (E10/S20 v R20) | 72/77 (93.5) | -53.00 (12.99) | 73/76 (96.1) | -50.00 (13.08) | 8 | -3.00 (-7.24, 1.24) |
| Protocol 058 (V10/20 v R20) | 476/492 (96.7) | -51.50 (11.13) | 478/495 (96.6) | -52.30 (12.27) | 6 | 0.80 (-0.69, 2.29) |
| Pooled result | Chi-square for heterogeneity: P=0.10 I 2 statistic with 95% uncertainty interval=63.2% | -0.56 (-4.13, 3.01) | ||||
V10/20=Vytorin 10/20, E10/S20=ezetimibe 10 mg/simvastatin 20 mg,
A40=atorvastatin 40 mg, R20=rosuvastatin 20 mg, SD=standard
deviation, WMD=weighted mean difference.
Results of mean change in TC:HDL-C ratio from baseline to
end point changes across the direct randomised trials (first-line
setting)
| Trial ID (comparison) | V10/20 or E10/S20 | A40 or R20 | End point (weeks) | WMD (95% CI) | ||
| n/N (%) | Mean (SD) | n/N (%) | Mean (SD) | |||
| Protocol 051 (V10/20 v A40) | 233/238 (97.9) | -40.00 (11.68) | 232/237 (97.9) | -37.10 (11.66) | 6 | -2.90 (-5.02, -0.78) |
| Protocol 077 (V10/20 v A40) | 238/247 (96.3) | NR | 241/254 (98.4) | NR | 6 | NC |
| Pooled result | Chi-square for heterogeneity: P=NA I 2 statistic with 95% uncertainty interval=NA | NC | ||||
| COMPELL (E10/S20 v R20) | 72/77 (93.5) | -43.00 (8.66) | 73/76 (96.1) | -40.00 (8.72) | 8 | -3.00 (-5.83, -0.17) |
| Protocol 058 (V10/20 v R20) | 476/492 (96.7) | -40.30 (10.02) | 478/495 (96.6) | -41.40 (10.04) | 6 | 1.10 (-0.17, 2.37) |
| Pooled result | Chi-square for heterogeneity: P=0.01 I 2 statistic with 95% uncertainty interval=85.0% | -0.75 (-4.75, 3.25) | ||||
V10/20=Vytorin 10/20, E10/S20=ezetimibe 10 mg/simvastatin 20 mg,
A40=atorvastatin 40 mg, R20=rosuvastatin 20 mg, SD=standard
deviation, WMD=weighted mean difference, NR=not reported, NC=not
calculable, NA=not applicable.
The PBAC noted patients treated with Vytorin 10/20 or ezetimibe 10
mg and simvastatin 20 mg concomitantly experience statistically
significantly greater percentage mean reductions in TC:HDL-C
compared with simvastatin 40 mg or atorvastatin 20 mg in the
second-line treatment setting. In the first-line setting patients
treated with Vytorin 10/20 or ezetimibe 10 mg/simvastatin 20 mg
experienced statistically significantly greater reductions in
LDL-C, and TC:HDL-C ratio (and statistically significantly greater
increases in HDL-C) than those treated with atorvastatin 40 mg. No
statistically significant differences in any of the reported
outcomes was observed between patients treated with Vytorin 10/20
or ezetimibe 10 mg/simvastatin 20 mg and those treated with
rosuvastatin 20 mg.
No significant differences in any adverse event outcomes reported
were observed between Vytorin 10/20 or ezetimibe 10 mg/simvastatin
20 mg and its comparators (simvastatin 40 mg, atorvastatin 20 mg
and 40 mg and rosuvastatin 20 mg).
9. Clinical Claim
The submission claimed that Vytorin 10/20 was superior in terms of
effectiveness compared with simvastatin 40 mg, atorvastatin 20 mg
and atorvastatin 40 mg and equi-effective compared with
rosuvastatin 20 mg. This was accepted by the PBAC.
The submission’s claim that Vytorin 10/20 is non-inferior in
terms of safety to all its nominated comparators was also accepted
as reasonable.
10.Economic Analysis
The submission presented a cost-minimisation analysis of Vytorin
(V)10/20 and rosuvastatin 20 mg and a stepped economic evaluation
for each of the other comparators i.e., V10/20 versus Simvastatin
(S)40, V10/20 v Atorvastatin (A)20, V10/20 versus A40.
The model was a Markov model with four health states dependent on
the presence or absence of Coronary Heart Disease (CHD) or
Cardiovascular Disease (CVD) and the cause of death.
The model transformed TC:HDL ratios to CHD events, deaths due to
CVD and mortality and estimates LYG and QALY.
The incremental cost-effectiveness ratios (ICER) per
Quality-Adjusted Life-Year (QALY) gained over 20 years for Vytorin
10/20 versus simvastatin 40 mg was estimated to be in the range of
$15,000 - $45,000.
For PBAC’s view see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of packs dispensed per
year to be at a cost to the PBS of between $10 – $ 30 million
in Year 5.
The PBAC considered this was a likely underestimate of the
financial implications.
12. Recommendation and Reasons
The PBAC considered that the choices of up titration of statin dose
from statin 20 mg or switching to a more potent statin as the main
comparators were appropriate.
The PBAC agreed that although the requested restriction would place
Vytorin 10/20 as a second-line treatment, the results of trials in
first line use were relevant, given that the outcome of interest is
the effect on LDL and then modelling survival benefits from this in
an appropriate (though different) population. The PBAC agreed that
the effect on LDL is not modified by whether use is first- or
second- line, although the size of any effect on survival would
be.
Therefore, in terms of effect on LDL (and TC:HDL-C ratio), the PBAC
accepted the submission’s claim that Vytorin 10/20 daily is
superior in terms of effectiveness compared with simvastatin 40 mg,
atorvastatin 20 mg and atorvastatin 40 mg and equi-effective
compared with rosuvastatin 20 mg daily. The submission’s
claim that Vytorin 10/20 is non-inferior in terms of safety to all
its nominated comparators was also accepted as reasonable.
The submission presented a cost-minimisation analysis of Vytorin
10/20 and rosuvastatin 20 mg and a stepped economic evaluation is
presented for each of the other comparators (i.e., Vytorin10/20
versus simvastatin 40 mg, Vytorin 10/20 versus atorvastatin 20 mg,
Vytorin 10/20 versus atorvastatin 40 mg). The PBAC noted
rosuvastatin is the least prescribed of the three PBS-listed
statins.
The submission presented the same model that has been previously
considered by the PBAC. The outcome from the randomised second-line
trials that was used in the modelled economic evaluation was the
percentage mean change in TC-HDL-C ratios.
The PBAC considered the time horizon of the model (70 years) to be
unreasonable, particularly given the age and health status of the
population in the modelled evaluation. Patients have an average age
of 71 years at baseline in the model, and the mortality rates
applied to this population may be underestimated, and thus the
incremental effect on survival overestimated. The Incremental Cost
Effectiveness Ratio (ICER) increased from the lower range of
between $15,000 - $45,000 to the upper range of between $45,000 -
$75,000 as the time horizon decreased.
The PBAC considered a 20-year time horizon was more appropriate
given the age and health status of the population in the modelled
evaluation, and the resulting ICER per QALY in the $15,000 -
$45,000 range to be high.
The PBAC noted the submission estimated the financial cost per year
of listing would be in the $10 – $30 million range by year 5
of listing. This was considered a likely underestimate as the
submission considered only substitution from simvastatin 40 mg,
atorvastatin 20 mg, atorvastatin 40 mg, rosuvastatin 20 mg and
pravastatin 40 mg and does not consider potential substitution from
concomitant use of ezetimibe 10 mg and 20 mg of other statins. As
these patients will be switching from two therapies (where two
co-payments were made) to a single combination therapy, with a
single co-payment, the costs to the PBS are likely to increase in
cases of this substitution. It was also noted that the total cost
of statin medications on the PBS in the 12 months to June 2008 was
in excess of $900 million.
The PBAC recalled that it had previously accepted cost-minimisation
claims for the listing of lipid lowering drugs on the basis of the
extent of LDL cholesterol reduction. The PBAC also recalled when
ezetimibe had been recommended for listing in June 2003, listing
was recommended on the basis of pricing being related to the extent
of LDL cholesterol reduction with ezetimibe compared with the
statins. The PBAC did not accept the submission’s claim of
cost-effectiveness at the requested price compared with
atorvastatin, particularly in the absence of clinical endpoint data
showing improved outcomes in terms of mortality or cardiovascular
events.
Further, in July 2005, the PBAC had again indicated its concern
with respect to the lack of direct clinical end-point data
available for lipid lowering drugs during its consideration of
atorvastatin. In July 2005, following the presentation of further
data, the PBAC advised that the only basis for judging whether the
price relativity could be further increased would be an incremental
cost-effectiveness analysis based on major cardiovascular events
measured directly in randomised trials rather than based on
predictions modeled from surrogate outcomes.
The comment in the recent article, Amid Lingering Questions,
FDA Reprieves LDL Cholesterol–Lowering Medication, Mitka
M, JAMA. 2009; 301(8):813-815, that the hopes for providing
evidence that ezetimibe/simvastatin affects clinical outcomes such
as myocardial infarction or death rests on results from the ongoing
Improved Reduction of Outcomes Vytorin Efficacy International Trial
(IMPROVE-IT), which has a completion date of 2012, was noted. The
PBAC noted that despite the FDA acceptance of LDL lowering as a
surrogate endpoint, there was ongoing unease in the medical
community concerning the translation of these data into overall
mortality and morbidity benefits.
The PBAC noted that not only was it required to take into account
effectiveness, comparative effectiveness and cost-effectiveness
during its decision making process, but also other relevant factors
such as financial cost to the PBS, and community need for a
product.
The Committee considered that, were ezetimibe with simvastatin
10/20 mg (Vytorin) to be recommended for listing, the health
benefits derived from its availability would be similar to the
health benefits associated with up-titration of a statin. However,
while both statins and ezetimibe lower lipid levels, the mortality
benefits of statins has been demonstrated, and up-titration with a
statin was the preferred approach. The current restriction allows
for ezetimibe to be introduced only where inadequate lipid lowering
had occurred at a dose of 40 mg or greater of a statin, or where
the statin dose is lowered to 20 mg per day or discontinued due to
the development of clinically important product-related adverse
events.
Therefore, the PBAC rejected the application on the basis of a lack
of clinical need, given the availability of statins to provide a
similar health benefit, that in terms of a cost-effectiveness
evaluation the listing would provide currently available benefits
at a higher cost, and the listing would place an additional
significant financial burden on the PBS.
The PBAC noted that the submission meets the criteria for an
Independent Review.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsors acknowledge the PBAC's acceptance of the clinical
efficacy and safety profile of Vytorin 10/20 and they will continue
to work with the PBAC to identify patient groups in which the use
of Vytorin 10/20 is considered appropriate.
A number of outcomes studies are currently under way and these
trials should provide data that demonstrate that lowering
cholesterol with Vytorin results in improved outcomes in terms of
mortality and cardiovascular events.
