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NEW FRONTIERS - 81st Scientific Sessions of the American Heart Association

New Orleans, Louisiana / November 9-12, 2008

Intensive lipid-lowering in individuals selected primarily for their elevated high-sensitivity C-reactive Protein (hsCRP) levels has provided one of the largest relative reductions in cardiovascular (CV) risk ever recorded in a primary prevention study. In the trial, called JUPITER (Justification of the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial, older individuals without hyperlipidemia and no history of CV disease but elevated levels of hsCRP were randomized to 20 mg rosuvastatin or placebo. Among those who received rosuvastatin, there was a 44% (HR 0.56, 95% CI: 0.46-0.69; P<0.00001) reduction in the primary composite end point of CV events and a 20% reduction (HR 0.80, 95% CI: 0.67-0.97; P=0.02) in death from any cause (Figure 1). The benefits were remarkably consistent across all subgroups.

“In apparently healthy persons without hyperlipidemia but who do have elevated hsCRP, rosuvastatin significantly reduced the risk of major CV events,” confirmed the senior investigator, Dr. Paul M. Ridker, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. “The treatment was well tolerated. Myopathy, hepatic injury and cancer did not occur more frequently with rosuvastatin despite the fact that half the patients had cholesterol levels below 55 mg/dL [1.4 mmol/L].”

The study is a dramatic demonstration that elevated hsCRP is a viable method of selecting individuals who can benefit from intensive lipid-lowering. In this primary prevention study which enrolled men over the age of 50 and women over the age of 60, the major criteria for entry were hsCRP >2.0 mg/L and LDL-C <3.4 mmol/L (<130 mg/dL). Entry was not only barred to patients with a history of CV disease but to those with diabetes. Although participants were allowed to have a history of hypertension if their blood pressure at entry was <190/100 mm Hg, many individuals who entered the study had no risk factor other than their age.

Of the 17,802 patients who were enrolled at 1,315 study sites in 26 countries including Canada, half were randomly assigned to rosuvastatin 20 mg q.d. and the other half took placebo. The study was terminated by the Data and Safety Monitoring Committee only 1.9 years into a planned five-year study because of the overwhelming advantage of rosuvastatin. In addition to the highly significant advantage for rosuvastatin for the primary composite end point of myocardial infarction (MI), stroke, arterial revascularization, hospitalization for unstable angina, or death from CV causes, risk reductions were large for the individual components. For example, the risk reductions were 65% for nonfatal MIs (P<0.00001), 54% for any MI (P=0.0002), 48% for any stroke (P=0.002), and 46% for any revascularization (P<0.0001).

Figure 1.

These large benefits were not accompanied by any significant safety issues. The relatively modest dose of rosuvastatin, although highly effective for reducing LDL, was both well tolerated and safe. The total proportion of patients experiencing any serious adverse event was slightly lower in the rosuvastatin group (15.2 vs. 15.5; P=0.6). There were no significant differences in regard to myopathy or muscle weakness, stiffness or pain. The rate of newly diagnosed cancers was almost identical (3.4% vs. 3.5%; P=0.51 for rosuvastatin vs. placebo) and the rate of death from cancer was significantly lower on rosuvastatin (0.4% vs. 0.75: P=0.02), although this latter result is likely to be a statistical anomaly.

“We have a great deal of safety data on the statins, and what we know is that these drugs are as safe as ASA, probably safer,” reported Dr. Jacques Genest, Jr., Director of Cardiology, McGill University, MUHC-Royal Victoria Hospital, Montreal, Quebec, and a senior co-author of the JUPITER study. He indicated that the results of the study contribute substantial reassurance to the large body of data that current statins and low LDL-C levels are safe.

In JUPITER, only 20 mg of active ingredient was enough to produce a median LDL-C reduction of 50%. It reduced hsCRP by a median 37%. The substantial effect of rosuvastatin against LDL-C and hsCRP was one of the reasons that this agent was selected for the trial. Although this study was designed to test elevated hsCRP as a marker for patients with normal lipid levels who would benefit from statins, it is possible that its anti-inflammatory effects as well as the lipid reductions contributed to the observed benefits.

The large patient population conferred JUPITER with the ability to detect even relatively uncommon side effects. Even though 25% of individuals randomized to rosuvastatin achieved an LDL-C <1.1 mmol/L (<44 mg/dL), active treatment was well tolerated. The only significant difference between rosuvastatin and placebo was a slight increase in HbA_1c (5.9 vs. 5.8; P=0.001) and physician-reported new cases of diabetes (3.0 vs. 2.4; P=0.01), both of which have been observed in most statin trials.

Nearly 40% of the JUPITER study population were women. When genders were compared, the relative reduction in risk, although statistically indistinguishable, was slightly greater among women. Similarly, there were no significant differences for the relative advantage of rosuvastatin over placebo for those older than age 65 compared to those younger, for those with hypertension compared to those without, and for North Americans compared to non-North Americans. There was also no difference between non-Caucasians, who represented almost 30% of the JUPITER population, when compared to Caucasians.

“The guidelines are now likely to change,” Dr. Genest reported. “We have to decide as a society what level of risk we are able to accept and what cost we are willing to pay for prevention.” Yet Dr. Genest did indicate that hsCRP is a useful risk stratifier that will be entered into routine clinical use.

Summary

In apparently healthy men over the age of 50 and women over the age of 60, elevated hsCRP identifies individuals who will achieve large CV risk reductions from intensive lipid lowering with rosuvastatin. At a relatively modest dose of 20 mg, rosuvastatin reduced LDL-C by a median of 50% to a level of 1.4 mmol/L. Both the therapy and these low levels of LDL-C were safe. In particular, there were no differences between rosuvastatin and placebo for muscle symptoms or other side effects reported with earlier-generation agents given at higher doses. Based on the large benefits associated with this degree of intensive lipid lowering, modifications in treatment guidelines are anticipated.