Should people at low risk of cardiovascular disease take a statin?

We want to thank Drs. Davis and Dietrich for raising important concerns about our analysis of the effect of statins in people at low risk of cardiovascular disease.

Based on CTT data published in 2012, we showed that statins do not reduce overall mortality in people whose 10-year risk of a major vascular event is less than 20%. Drs. Davis and Dietrich are correct that patients treated with rosuvastatin in the JUPITER trial experienced a significant reduction in all-cause mortality compared to those in the control group. However, the data from this study were included in the CTT meta-analysis of 2012, so singling out the all-cause mortality findings from this study alone would undermine the purpose of the meta-analysis.

That said, there are other issues with the JUPITER trial that merit consideration. At the time the study was prematurely stopped, there was absolutely no difference between the two groups in the number of deaths due to cardiovascular causes—MI and stroke—with 12 such deaths in each group. (This can be calculated by subtracting “Nonfatal myocardial infarction” from “Any myocardial infarction” and doing the same for nonfatal and any stroke from data in Table 3 of the JUPITER trial report in NEJM. ) The entire difference in all-cause mortality in the JUPITER trial was, inexplicably, due to differences in non-cardiovascular mortality.

Further, the JUPITER trial reported more than twice the rate of myocardial infarction in control group patients, but the mortality rates for MI in the two groups are highly anomalous. Again from Table 3 of the NEJM article, patients treated with rosuvastatin had a post-MI mortality rate of 29% (9 fatal MIs/31 total MIs), which is lower than the 40-50% mortality rate that would be expected. But the MI mortality rate in the control group defies credulity: 6 fatal MIs out of a total of 68 MIs, for a mortality rate of 8.8%. This strongly suggests that there was a difference in ascertainment of MI between the two groups. The unrealistically low mortality rate for myocardial infarction in the control group calls into question the accuracy of the myocardial infarction rates. These questions were raised in an article published in the Archives of Internal Medicine in 2010, but there was no response from JUPITER trialists.

We believe that Drs. Davis and Dietrich have conflated “serious adverse events” with “major adverse cardiovascular events.” Serious adverse events— deaths from all causes, hospital admissions, prolongations of admission, cancer, or permanent disability—are measured in all studies, but unfortunately reported in few of the statin studies. The largest of the studies to report the incidence of serious adverse events, JUPITER, found no difference between the active treatment and control groups. The 2013 Cochrane review of statins for primary prevention reports no difference between the incidence of serious adverse events (including cardiovascular events) noted in meta-analyses of all studies that reported serious adverse event rates.

There is not a uniform definition of “MACE” or major adverse cardiovascular events. In our analysis, we chose to limit the definition to “hard events”—cardiovascular death, myocardial infarction, and stroke. These events have a major impact on people’s lives, should have minimal ambiguity in adjudication, and are not vulnerable to geographical variation or bias due to unblinding of treatment allocation (LDL levels are lower in patients in the treatment arms of the studies).

Our analysis in BMJ was published 3 weeks before the release of the updated U.S. Guidelines for cholesterol-lowering. We had no advanced knowledge of the forthcoming recommendations. We based our comments on the 2012 CTT meta-analysis, an associated editorial, and the 2013 Cochrane Review of statins for primary prevention. We had no idea that the updated guidelines would set the threshold for recommending statin therapy at 7.5% 10-year risk of major vascular event guidelines.

And finally, Drs. Davis and Dietrich are mistaken that we discussed people with 10 year risk below 5% “extensively.” Their confusion is understandable because the relevant publications present both 5-year and 10-year percentage risk data. Frankly, BMJ editors asked if we could avoid this potential confusion by presenting either 5-year or 10-year baseline risk data. In our opinion, doing so would have compromised the integrity of the data too much, and we presented the data as they were reported in the original articles. We apologize for the confusion.