Lipid Studies That Rocked My World Gabor Gyenes Medicine 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, unfortunately I 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 of JUPITER
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 Roles of CRP Endothelial Dysfunction Vasodilation NO Endothelial activation Monocyte adhesion Endothelial progenitor cells Plaque progression Monocyte migration VSMC proliferation Plaque Rupture /Thrombosis Cap thinning TF secretion Fibrinolysis Progression of atherosclerosis NO: Nitric oxide, VSMC: Vascular Smooth Muscle Cell, TF: Tissue factor Bisoendial RJ, Kastelein JJP, Stroes ESG. Atherosclerosis 2007; 195:e10-18 Packard RRS, Libby P. Clin Chem 2008; 54:24-38 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 1.00 Probability of eventfree survival 0.99 0.98 0.97 Low LDL-C, low CRP High LDL-C, low CRP Low LDL-C, high CRP 0.96 0 High LDL-C, high CRP Women s Health Study data LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein Median LDL-C=3.2 mmol/l (124 mg/dl) Median CRP=1.5 mg/l Ridker PM et al. N Engl J Med 2002; 347: 1557 1565.
JUPITER study design No history of CAD men 50 yrs women 60 yrs LDL-C <3.36 mmol/l CRP 2.0 mg/l Placebo run-in Rosuvastatin 20 mg (n~8900) Placebo (n~8900) Visit: Week: 1 6 2 4 3 0 4 13 6-month intervals Final 3 4 y Lead-in/ eligibility Randomisation Lipids CRP Tolerability Lipids CRP Tolerability Lipids CRP Tolerability HbA 1C Primary Endpoint was the composite of: cardiovascular death, stroke, MI, unstable angina and arterial revascularisation
JUPITER - Baseline laboratory parameters * Rosuvastatin Placebo n=8901 n=8901 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) HbA 1c (%) 5.7 (5.4-5.9) 5.7 (5.5-5.9) Glomerular filtration rate, (ml/min/1.73m 2 ) 73.3 (64.6-83.7) 73.6 (64.6-84.1) 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.
JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal MI, unstable angina or arterial revascularization Percent of patients with primary endpoint 9 8 7 6 5 4 3 2 1 0 Hazard Ratio 0.56 (95% CI 0.46-0.69) P<0.00001 Placebo 0 1 2 3 4 5 Years Number at risk RSV 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174 Rosuvastatin 20 mg NNT for 2y = 95 5y* = 25 *Extrapolated figure based on Altman and Andersen method Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER - Total Mortality Death from any cause Percent total mortality 7 6 5 4 3 2 1 Hazard Ratio 0.80 (95% CI 0.67-0.97) p=0.02 Placebo Rosuvastatin 20mg 0 0 1 2 3 4 5 Years Number at risk RSV 8901 8787 4312 1602 676 227 Placebo 8901 8775 4319 1614 681 246 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 10 LDL-C HDL-C TG hscrp Percentage change from baseline (%) 0-10 -20-30 -40-50 -60 50% p<0.001 4% p<0.001* 17% p<0.001 37% p<0.001 *P-value at study completion (48 months) = 0.34 Ridker P et al. N Eng J Med 2008;359: 2195-2207.
JUPITER Tolerability and safety data Placebo [n=8901] Rosuvastatin p-value [n=8901] Adverse Events, (%) Any serious adverse event 15.5 15.2 0.60 Muscle weakness, stiffness, pain 15.4 16.0 0.34 Myopathy 0.1 0.1 0.82 Rhabdomyolysis 0.0 <0.1 * ---- Newly diagnosed cancer 3.5 3.4 0.51 Death from cancer 0.7 0.4 0.02 Gastrointestinal disorders 19.2 19.7 0.43 Renal disorders 5.4 6.0 0.08 Bleeding 3.1 2.9 0.45 Hepatic disorders 2.1 2.4 0.13 Other events, (%) Newly diagnosed diabetes ** 2.4 3.0 0.01 Haemorrhagic stroke 0.1 0.1 0.44 *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 reported Lancet 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, BScPharm 1, Glen J. Pearson, BSc, BScPharm, PharmD, FCSHP 2, Theresa L. Charrois, BScPharm, MSc, ACPR 2, Gabor Gyenes, MD, PhD 2, Sheri L. Koshman, BScPharm, PharmD, ACPR 2 1 Regional Pharmacy Services, Alberta Health Services; 2 Division 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) The mean atorvastatin equivalent dose at discharge was 33 mg. * Assumed 3 patients without statin doses documented PTA were not IST
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, extendedrelease 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
Heart Protection Study: Safety 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 Collaborative Group. Lancet. 2002;360:7-22.