Lipid Studies That Rocked My World

Gabor GyenesMedicine Grand Rounds

May 27, 2011

Disclosure of Conflicts of Interest

I have received travel grants and honoraria from sanofi-aventis, Pfizer,

Servier, Merck, Procter & Gamble, Biovail, AstraZeneca, Medtronic,

Novartis, Boehringer-Ingelheim and Merck/Frosst/Schering

No stocks or bonds, unfortunatelyI was the Primary Investigator of studies

sponsored by Pfizer, Boehringer-Ingelheim, sanofi-aventis, and currently,

GSK

Objectives

Primary prevention• JUPITER

Secondary prevention• PROVE-IT• Meta-analysis 2010

How (un)well we do this• U of A study

You tell me what to do - ACTION

“The” Primary Prevention Study We’d Love to Ignore

MGR\Drops of Jupiter.mp4

Drops ofJUPITER

JUPITER

JUPITER was the first large study to examine the role of statin therapy in individuals with low to normal LDL-C levels (mean of 2.7 mM/L) but with elevated hsCRP

It assessed the long-term impact of rosuvastatin 20 mg/d in individuals who, based on Framingham risk scores, did not qualify for lipid-lowering treatment according to current guidelines

Does elevated hsCRP identify a patient who would benefit from statin therapy?

Ridker P et al. N Eng J Med 2008;359: 2195-2207

CRP contributes to all stages of atherosclerosis

NO: Nitric oxide, VSMC: Vascular Smooth Muscle Cell, TF: Tissue factor

Bisoendial RJ, Kastelein JJP, Stroes ESG. Atherosclerosis 2007; 195:e10-18Packard RRS, Libby P. Clin Chem 2008; 54:24-38

Roles of CRP

Progression of atherosclerosis

Endothelial Dysfunction Vasodilation

NO

Plaque Rupture /Thrombosis

Cap thinning TF secretion Fibrinolysis

Plaque progression Monocyte migration VSMC

proliferation

Endothelial activation

Monocyte adhesion

Endothelial progenitor cells

For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

Cardiovascular event-free survival in women using combined LDL-C and CRP measurements

LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive proteinMedian LDL-C=3.2 mmol/L (124 mg/dL)Median CRP=1.5 mg/LRidker PM et al. N Engl J Med 2002; 347: 1557–1565.

1.00

0.99

0.98

0.97

0.96

0

Low LDL-C, low CRP

High LDL-C, high CRP

High LDL-C, low CRP

Low LDL-C, high CRP

Probability of event-free survival

Women’s Health Study data

JUPITER – study design

LipidsCRP

Tolerability

LipidsCRP

TolerabilityHbA1C

Placebo run-in

1–6

2–4

30

413

Final3–4 y

6-monthintervals

Visit:Week:

Randomisation LipidsCRP

Tolerability

Rosuvastatin 20 mg (n~8900)

Placebo (n~8900)

Lead-in/eligibility

No history of CAD men ≥50 yrs

women ≥60 yrsLDL-C <3.36 mmol/L

CRP ≥2.0 mg/L

Primary Endpoint was the composite of: cardiovascular death, stroke, MI, unstable angina and arterial revascularisation

Total cholesterol (mg/dL) 4.81 (4.34-5.17) 4.78 (4.37-5.15)

LDL cholesterol (mg/dL) 2.69 (2.43-3.08) 2.69 (2.43-3.08)

HDL cholesterol (mg/dL) 1.27 (1.03-1.55) 1.27 (1.03-1.55)

Triglycerides (mg/dL) 1.33 (0.96-1.91) 1.33 (0.97-1.90)

hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2)

Glucose (mg/dL) 5.88 (5.5-6.4) 5.88 (5.5-6.4)

HbA1c(%) 5.7 (5.4-5.9) 5.7 (5.5-5.9)

Glomerular filtration rate,(ml/min/1.73m2) 73.3 (64.6-83.7) 73.6 (64.6-84.1)

Rosuvastatin Placebon=8901 n=8901

JUPITER - Baseline laboratory parameters*

For hsCRP, values are the average of the values obtained at two screening and visits

*All values are median (interquartile range) or N (%). Ridker P et al. N Eng J Med 2008;359: 2195-2207

For complete therapeutic and safety information please consult the CRESTOR® Product Monograph.

0

1

2

3

4

5

6

7

8

9

0 1 2 3 4 5Years

Placebo

Rosuvastatin 20 mg

JUPITER - Primary EndpointTime to first occurrence of a CV death, non-fatal stroke, non-fatal

MI, unstable angina or arterial revascularizationP

erce

nt

of p

atie

nts

wit

hp

rim

ary

end

poi

nt

Number at riskRSV 8901 8412 3893 1353 538 157Placebo 8901 8353 3872 1333 531 174

Hazard Ratio 0.56 (95% CI 0.46-0.69)P<0.00001

Ridker P et al. N Eng J Med 2008;359: 2195-2207

NNT for 2y = 955y* = 25

*Extrapolated figure based on Altman and Andersen method

0

1

2

3

4

5

6

7

0 1 2 3 4 5Years

Placebo

Rosuvastatin 20mg

JUPITER - Total MortalityDeath from any cause

Per

cen

t to

tal m

orta

lity

Number at riskRSV 8901 8787 4312 1602 676 227Placebo 8901 8775 4319 1614 681 246

Hazard Ratio 0.80 (95% CI 0.67-0.97)p=0.02

Ridker P et al. N Eng J Med 2008;359: 2195-2207

.

JUPITER

Effects on LDL-C, HDL-C, TG and hsCRP at 12 months;

Percentage change between rosuvastatin and placebo

-60

-50

-40

-30

-20

-10

0

10 LDL-C HDL-C TG hsCRP

Per

cen

tag

e ch

ang

e fr

om b

asel

ine

(%)

50%

4%

17%

37%

p<0.001

p<0.001*

p<0.001

p<0.001

*P-value at study completion (48 months) = 0.34 Ridker P et al. N Eng J Med 2008;359: 2195-2207

.

JUPITERTolerability and safety data

Adverse Events, (%)Any serious adverse event 15.5 15.2 0.60Muscle weakness, stiffness, pain 15.4 16.0 0.34Myopathy 0.1 0.1 0.82Rhabdomyolysis 0.0 <0.1* ----Newly diagnosed cancer 3.5 3.4 0.51Death from cancer 0.7 0.4 0.02Gastrointestinal disorders 19.2 19.7 0.43Renal disorders 5.4 6.0 0.08Bleeding 3.1 2.9 0.45Hepatic disorders 2.1 2.4 0.13

Other events, (%)Newly diagnosed diabetes** 2.4 3.0 0.01Haemorrhagic stroke 0.1 0.1 0.44

Placebo Rosuvastatin p-value[n=8901] [n=8901]

*Occurred after trial completion; **physician reported newly diagnosed diabetes Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER – summary and perspectives

In these patients with “normal” LDL-C and elevated CRP levels the administration of Crestor 20 mg/d resulted in:

A 50% LDL-reduction

A 44% reduction in the primary endpoint of major cardiovascular events

A 20% reduction in total mortality (p=0.02)

And it was well tolerated

This is a public health policy issue: how much are we willing to pay to prevent one CV event in an already low risk population? Screening plus treatment costs…

However, we need to offer CRP screening to these individuals if they’re willing to take a statin long-term

SECONDARY PREVENTION

MGR\The hardest part.mp4

The Paradigm Shift: PROVE-IT-TIMI 22 4162 pts w/ ACS randomized to pravastatin 40mg

vs. atorvastatin 80mg Pravastatin arm achieved then current Guideline

recommendations at LDL<2.5 mM/L Lipitor arm achieved median LDL of 1.6 mM/L, or

an on-treatment mean of 1.8 D/MI/UA/revascularization: 16% RRR (p = 0.005)

in 2 years The price: 3.3% vs. 2.7% LFT↑

NEJM 2004;350:1495.

Reasons Why PROVE-IT Convinced Me

The study was designed to show non-inferiority of pravachol

It was sponsored by BMS not Pfizer Not placebo-controlled yet so significant results REVERSAL (similarly designed IVUS study)

showed vascular benefits although only in those w/ LDL<1.8

NEJM 2004;350:1495.

Updated Cholesterol Treatment Trialist’s (CTT) Meta-analysis

Meta-analyses of individual participant data; • A) 5 studies of less vs. more intensive statin

therapy; w/ >1,000 participants (39,612); >2 yrs F/U (5.1 yrs)

• B) 21 studies (129,526 pts) of statin therapy vs. placebo w/ 4.8 yrs of mean F/U

Calculated the average risk reduction and the ARR/1 mM/L at one year as well

Safety data were also reportedLancet 2010; 376: 1670–81.

CTT Meta-analysis A 0.51 mM/L further LDL-reduction (in the first year) resulted

in:• 15% (p<0.0001) RRR of vascular events incl.• 13% RRR of coronary death or non-fatal MI (p<0.0001) • 19% RRR in coronary revascularisation (p<0.0001), • 16% RRR in ischemic stroke (p=0.005)

The per mM/l reductions were similar to those in the B trials so they were all combined for further analysis: a 22% reduction of major vascular events/1.0 mM/L LDL-C reduction was found in all patients including those with LDL<2 mM/L on the less intensive or control regimen

Lancet 2010; 376: 1670–81.

Combined Results - 2 All-cause mortality was reduced by 10%/ 1.0 mM/L

LDL reduction mainly d/t reductions in CHD deaths (RR 0.80, 99%

CI 0.74–0.87; p<0.0001) no significant effect on deaths d/t stroke or other

vascular causes No effects on deaths due to cancer, other non-vascular

causes or on cancer incidence, even at low LDL levels NS excess of hemorrhagic stroke (257 vs. 220; RR 1.12,

95% CI 0.93–1.35; p=0.2.) 10 (of 14 altogether) rhabdo cases w/ Zocor 80!

Lancet 2010; 376: 1670–81.

Practical Consequences

This should be convincing enough to us who initiate treatment for the high-risk patients that we should follow the ALARA rule

To me this means that in pts w/ vascular disease I must initiate Lipitor 80mg (maybe Crestor 40mg) therapy in hospital because a lower dose means intentional under treatment that would disadvantage the patient long-term – the dose will never be uptitrated

So how well do we do this?

The Application of Knowledge

MGR\DT A nightmare to remember.mp4

Intensive Statin Therapy (IST) in Acute Coronary Syndrome Patients

Admitted to a Tertiary Care Centre: Current Practice Pattern Evaluation

Jennifer R. Shiu, BScPharm1, Glen J. Pearson, BSc, BScPharm, PharmD, FCSHP2, Theresa L. Charrois, BScPharm, MSc, ACPR2, Gabor Gyenes,

MD, PhD2, Sheri L. Koshman, BScPharm, PharmD, ACPR2

1Regional Pharmacy Services, Alberta Health Services; 2Division of Cardiology; University of Alberta, Edmonton, AB

Methods

• Retrospective chart review of randomly selected ACS (ICD 20 – 25) patients in hospital and in early follow up after discharge

• Conducted in 2 phases at the University of Alberta Hospital (UAH) in Edmonton, AB• Phase 1: retrospective chart review of ACS patients

admitted• Phase 2: chart review of cardiologist follow–up clinic

letters in patients started on IST during hospitalization

Methods

Inclusion Criteria

• Adults admitted to cardiology wards at UAH between November 1, 2007 and October 31, 2008 with a most responsible diagnosis of an ACS

• Phase 2:

• Started on IST (atorvastatin 80 mg or simvastatin 80 mg) during hospitalization

Exclusion Criteria• Transferred to another hospital• Admitted or transferred to CV

surgery wards• Death during index

hospitalization

• Phase 2:• Not followed by a cardiologist

at UAH on discharge summary

• No scheduled follow–up cardiologist visit on discharge summary

Table 2: Statin Utilization Patterns (n = 111)

IST (%) Other Statin/No IST (%)

No Statin (%)

Prior to Admission* 7 (6.3) 45 (40.5) 59 (53.2)

At Discharge 53 (47.7) 50 (45.0) 8 (7.2)

* Assumed 3 patients without statin doses documented PTA were not IST

•The mean atorvastatin equivalent dose at discharge was 33 mg.

Figure 3: Phase 2 Results – Newly Discharged on IST

The most common reason for IST DC at F/U was “elevated LFT”.However, no LFT elevation was >3x ULN.

Conclusions

• Overall, the majority of post ACS patients are treated with statins (93%)• However, IST utilization (52%) in the post ACS

population appears to be suboptimal in eligible patients

• Newly initiated IST shows poor persistence in follow–up after discharge, even though most patients remain on a statin

• Reasons for this treatment gap need to be further elucidated

My Conclusions Registry studies and our own experience shows

that we are disadvantaging our patients by not even trying to use the highest dose of potent statins

This practice also sends the wrong message across – if we are afraid of using the highest dose others will be too

Think of other fields (HTN, HF, etc.) where we’ve been through these problems and the resolution has always been that we started to do what’s right and everyone else followed suit

The Most Recent Sh(R)ocks A trial of extended-release niacin (Niaspan, Abbott)

given in addition to statin therapy… has been halted prematurely, 18 months ahead of schedule, because niacin offered no additional benefits in this patient population.

AIM-HIGH was a five-year study of almost 3500 patients.

The DSMB concluded that "high-dose, extended-release niacin offered no benefits beyond statin therapy alone in reducing cardiovascular-related complications in this trial. The rate of clinical events was the same in both treatment groups, and there was no evidence that this would change by continuing the trial."

Further Failures Fibrates have no significant outcome benefit,

maybe up to 10% by the most optimistic study Torcetrapib: increases mortality and ineffective

in decreasing CIM thickness Dalcetrapib: no improvement in endothelial fx’n Ezetrol: still no positive data although its

negative trials should be dismissed Omega-3 FAs added to statins: no effect Bottom line: we have no alternatives to statins

What Should We Do?

We need ACTION!!!MGR\Action.mp4

The SWEET

Placebo Simvastatin(n=10,267) (n=10,269) P Value

Liver ALT 32 (0.31%) 43 (0.42%) NS>4x ULN

Muscle CK 6 (0.06%) 11 (0.11%) NS>10x ULN

Myalgia/6 mo ~6-7% (Σ32.9%) ~6-7% (Σ:33.2%) NS

Cancer deaths 345 (3.4%) 359 (3.5%) NS

Heart Protection Study: Safety

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.