Statin use is centre stage again in the cardiology arena, as witnessed at the American College of Cardiology (ACC) 58th Annual Scientific Session, 29-31 March, Orlando, USA. This year’s meeting attracted 25,000 attendees (15,000 cardiac specialists), down by 4,000 from last year, attesting to the weakened economy. Reviewed below are three statin-related sessions.
JUPITER: New analysis
In patients (men ≥50 years, women ≥60 years) without prior cardiovascular disease or diabetes, the benefits of rosuvastatin extend to preventing venous thromboembolism (VTE), according to analysis of the JUPITER (Justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). In the initial analysis of JUPITER, the primary endpoint of myocardial infarction, stroke, unstable angina/revascularisation, and cardiovascular death was reduced 44% as compared to placebo (p<.00001), with an NNT (number needed to treat to prevent one adverse event) of 25.
JUPITER included 17,802 patients with no prior cardiovascular disease or diabetes, and with LDL <130mg/dL and hsCRP (high sensitivity C-reactive protein) ≥2mg/L. According to lead investigator Paul Ridker, Brigham and Women’s Hospital, Boston, USA, “The JUPITER trial was specifically designed to address whether statin therapy might be effective in preventing major cardiovascular events among a population that does not qualify for statin therapy because they already have LDL-C levels <130mg/dL (the treatment target in primary prevention), yet are at high risk due to elevated levels of the inflammatory biomarker hsCRP. In prior work from more than a dozen cohorts worldwide – including in the Framingham Heart Study – those with elevated levels of hsCRP have consistently been shown to be at increased vascular risk, even if cholesterol levels are low.”
Venous and arterial thrombosis are both common, serious age-related events that often co-occur and share some risk factors, noted Robert J Glynn, biostatistician at the Brigham and Women’s Hospital and Harvard Medical School. The need for a prospective randomised trial in VTE is borne out by the fact that venous thromboembolism observational and case-control studies with statins have not always shown reduced risk. Therefore, symptomatic venous thromboembolism was included as a prespecified secondary endpoint in JUPITER. Venous thromboembolism events were classified as “provoked” (occurring in the presence of trauma, hospitalisation or surgery within three months before diagnosis – with no malignancy diagnosed before or up to three months after the VTE) or unprovoked.
Fewer venous thromboembolisms were reported in the rosuvastatin group than in the placebo group (34 vs. 60, 43% reduction, p=.007). The reduction with rosuvastatin was significant, as well, for provoked venous thromboembolisms (48% reduction, p=.03), with a strong trend for unprovoked VTE (39% reduction, p=.09). The rate of pulmonary embolism was similar between statin and placebo (17 vs. 22, 23% reduction, p=.42), and deep vein thrombosis was significantly lower in the statin group (17 vs. 38, 55% reduction, p=.004). Bleeding was similar for both groups, with 258 events in the rosuvastatin group and 275 in the placebo group (p=.45). When VTE and total mortality at 4.5 years were combined with the JUPITER primary endpoint of myocardial infarction, stroke, unstable angina/revascularisation, and cardiovascular death, there were 163 fewer events in the statin arm (320 rosuvastatin, 483 placebo, p<.00001). The NNT was 18.
Glynn concluded that adding prevention of VTE and death to the rosuvastatin treatment target “increases the estimated benefit of statin use.”
“I’m impressed with the NNT and with the apparent early separation of curves,” stated ACC panellist Harvey D White, Green Lane Hospital, Auckland, New Zealand. Although, when asked whether this is a class effect, Glynn replied: “I have no idea.” At the ACC press conference, Ridker said it was likely a class effect.
Ridker also said: “Until JUPITER, no specific recommendations for therapy beyond advice for diet, exercise, and smoking cessation could be made to such individuals. We now know that statin therapy is highly effective at preventing heart attacks, strokes, and all-cause mortality among this previously ignored patient group.”
Treating to new targets
The TNT (Treating to new targets) trial showed intensive lipid lowering with atorvastatin 80mg to significantly lower the incidence of cardiovascular disease compared with atorvastatin 10mg in stable coronary heart disease patients aged 65 or older. That analysis, said Nanette K Wenger, Emory University School of Medicine, Atlanta, USA, assessed time to first events. Patients in this population, however, often have a series of cardiovascular events. To determine potential benefits over time of the higher statin dose, Wenger conducted a posthoc analysis looking at the trial period after first cardiovascular events.
TNT investigators randomised 3,809 subjects aged 65 and older to atorvastatin at either 10 or 80mg daily and followed them for a median of 4.9 years. The time-to-event analysis estimated treatment hazard ratios for first through fifth cardiovascular events. Included events encompassed coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularisation procedure, procedure-related infarction or documented angina, cerebrovascular events (fatal or nonfatal stroke, transient ischaemic attack), peripheral artery disease, or hospitalisation with primary diagnosis of congestive heart failure.
First events were reported among 1,130 stable coronary heart disease patients aged 65 years or older. The most commonly experienced endpoint as a first event was angina (171 for 80mg/180 for 10mg). Overall, coronary revascularisation was most common (300 for 80mg/437 for 10mg). Relative risk of a first cardiovascular event was reduced by 23% (p<.0001) in the higher-dose group as compared with the lower-dose group. The benefit was found for second through fifth events, although the difference between treatments at the fifth event was no longer statistically significant, presumably because of the small number of events.
“Treatment with atorvastatin 80mg continued to reduce the risk of any cardiovascular event over time compared with atorvastatin 10mg among patients 65 years or older,” Wenger concluded. She said further that the data show that the benefits of long-term intensive statin therapy are maintained after multiple cardiovascular events in this population.
“Many patients in Europe and Canada, the majority of whom are at high-risk for cardiovascular events, do not reach their LDL-C goals in spite of statin therapy.” This conclusion, voiced by Anselm K Gitt, University of Heidelberg, Germany, arose from the DYSIS (Dyslipidemia international study), a study examining more than 22,000 outpatients in Europe and Canada consecutively treated for dyslipidemia. The analysis revealed that a majority were not reaching lipid targets.
DYSIS was conducted at 2,987 centres, with most patients (73.6%) treated by primary care physicians. All patients were ≥45 years; all were currently receiving a statin and had documented fasting lipid profiles performed after they had been receiving statins for at least three months. Investigators examined the prevalence of persistent lipid abnormalities according to ATP III risk profile criteria (CHD or risk equivalent/2+ risk factors/0-1 risk factors). A large majority of patients (70%) were in the highest risk group (n=15,365), with about 19% and 11% in the 2+/0-1 risk factor groups, respectively. Most patients were receiving simvastatin (47.7%) or atorvastatin (28%). Nonstatin lipid therapies, such as ezetimibe, fibrates, nicotinic acid, and bile acid sequestrants, were taken by 13.5% of patients.
Investigators used ATP III LDL-C definitions for “not at LDL-C goal” for the three risk groups as follows: ≥100/130/160mg/dL. For all groups, low HDL-C was defined as <40/50mg/dL, and elevated triglycerides as ≥150mg/dL. Among patients with total lipid profiles (n=19,196) in the highest risk category, LDL-C did not reach target level in 43.3%, and in 35.7%/16.7% of those with 2+/0-1 risk factors. Among those not reaching LDL-C goals, two-thirds had abnormal HDL-C and/or triglyceride levels.
Commenting on the findings in an interview, Gitt said: “There is a lot of space for improvement, either by increasing doses, or by adding ezetimibe or other nonstatin lipid-lowering drugs. We now have to encourage physicians to treat to target rather than just insuring that the right drugs are being taken.”