Primary Care Corner with Geoffrey Modest MD: IMPROVE-IT trial ezetimibe

By: Dr. Geoffrey Modest

So, at long last, the IMPROVE-IT trial has been published: the one comparing simvastatin plus ezetimibe vs simvastatin alone in high-risk patients (this was the study that came out as the block-buster, high-profile study at the Am Heart Assn meetings last November –7 months ago!!!, but was notably not published simultaneously, for remarkably opaque reasons….. see DOI: 10.1056/NEJMoa1410489). Ezetimibe decreases absorption of cholesterol from the GI tract and in prior studies lowered LDL by around 23-24%. This was a large double-blind study of patients recently hospitalized for an acute coronary syndrome and already had pretty good lipids initially. details:

–18,144 patients from 1147 sites in 39 countries (mean age 64, 76% male, 84% white, BMI 28, mean LDL was 93.8 mg/dl, 62% had hypertension and 27% diabetes, 33% current smoker, 35% on statin and 42% on aspirin prior to ACS), hospitalized for an acute coronary syndrome (acute MI with or without ST-segment elevation, or high-risk unstable angina) within the past 10 days, whose LDL was 50-100 mg/dl if on lipid-lowering therapy, otherwise up to 125 mg/dl. Randomized to simvastatin 40 vs simvastatin 40 plus ezetimibe 10 (combo group) — though some patients did receive the 80mg dose of simvastatin prior to the FDA warning in 2011, in up to 27% in the simvastatin monotherapy group. Followed median of 6 years.

–Results:

–achieved LDL in simvastatin group was 69.5 mg/dl; in combo group was 53.7 mg/dl (a 24% reduction, as anticipated). Also decreases in triglycerides, non-HDL cholesterol, apo B, hs-CRP levels)

–primary endpoint (composite of: death from cardiovascular disease; major coronary event such as nonfatal MI, documented unstable angina, or coronary revascularization; or nonfatal stroke): 32.7% with simvastatin-ezetimibe vs 34.7% with simvastatin (absolute risk reduction of 2 percentage points, with HR 0.96 (0.89-0.99, p=0.016), a 6% decrease. Benefit evident after 1 year, curves paralleled after that (ie no increasing ezetimibe effect over time). so, number-needed-to-treat of 50 patients for 7 years to prevent one event.

–in terms of specific individual outcomes (tertiary endpoints), the only ones achieving statistical significance were: any MI, nonfatal MI, ischemic stroke, hemorrhagic stroke, and urgent coronary revascularization

–also, buried in the supplementary materials, subgroup analyses revealed there were statistically significant differences only in the following:

–only in those >=75yo (n=2798, 11% reduced risk with combo therapy)

​–only in females (n=4416, 11% reduced risk with combo therapy)​

​–only in nonsmokers (n=12154, 9% reduced risk with combo therapy)​

–only in those with diabetes (n=4953, 14% reduced risk with combo therapy)

–only in those without prior stroke (n=12154, 9% reduced risk with combo therapy)

 ​–only in those with hypertension (n=11137, 9% reduced risk with combo therapy)

–only in those with creatinine clearance <60 (n=3261, 12% reduced risk with combo therapy)

–adverse event rate was similar in the 2 groups (no statistically significant differences, including myopathy, rhabdo, cancer, LFT changes). 10% in each group discontinued therapy from adverse events.

Comments:

–this study basically confirms the concept of treating-to-goal (I hate to say that “I told you so”, but will reluctantly do so in this case). But brings up a few issues:

–their figure 2 shows that the achieved LDL with added ezetimibe falls on the line of the achieved LDL line with statins (see following figure). This confirms other empirical observations that, even though statins have many pleiotrophic effects beyond lowering LDL (and some suggest that only 50% of the statin effects can be explained by the LDL effect), it really is the LDL which is predictive of future events, whether achieved by statins or ezetimibe (unless ezetimibe had similar pleiotrophic effects….)

 ebmgraph

(Cannon et al., 2015)

–what is the correct LDL goal?? the short answer is “who knows??”.

–it is clear that those at higher risk  benefit dramatically by taking statins by lowering their risk 30+%, but they still have a higher residual risk than those at lower initial risk.

–the data from the PCSK9 drugs shows that achieving an LDL of 48 is both clinically efficacious and without significant adverse events (see blog: here)

–so, what makes sense?:  I guess at this point that lowering the LDL to 100 mg/dl in primary prevention is reasonable. In those with evident atherosclerotic disease (CAD, PAD, stroke) or with diabetes, it probably would be useful to lower it more, perhaps to the 70 mg/dl range. and in those at really high risk, such as in the IMPROVE-IT study, or those with evident atherosclerotic disease with lots of ongoing risk factors that they are unable to modify (eg smoking), to shoot for a lower goal.

–does the achieved HDL play a role?

–the TNT (Treating to New Targets trial) found that, controlling for the HDL level, the achieved LDL seemed to determine the cardiovascular risk. but HDL, which seems to be taking a beating in the press, was actually important: the number of clinical events was the same if the achieved LDL were >100 mg/dl but the HDL were >=55 as if the achieve LDL was <70 with an HDL <38. And this was independent of whether the patient were on atorvastatin 10mg or 80mg. see the graph below (see n engl j med 2007:357;13), though this is a secondary analysis.

ebmgraph2

(Barter et al., 2007)

–does it make sense to generalize from the very high-risk individuals in IMPROVE-IT to the rest of the people we would consider putting on medications to lower lipids??

–again, “who knows?”. But seems to me to be pretty likely.  That being said, the IMPROVE-IT study was a poster-child of a drug company sponsored study. It added an unknown but likely useful lipid-lowering agent to an inferiorly-dosed statin in a combination pill made by the drug company. And as of 11/10/14 (prior to the release of IMPROVE-IT and likely subsequent dramatically increased revenues), the Wall Street Journal reported that the “sales of Zetia were $1.99 billion for the first nine months of 2014, while sales of Vytorin were $1.15 billion for the same period”.  One major concern I have is that in this huge, longterm study, the ezetimibe addition had only a small effect in these patients (who, admittedly, were already at a pretty low LDL level on just simvastatin), but there were pretty dramatic differences by subgroup (ie, no statistically significant effect of adding ezetimibe if nondiabetic, nonhypertensive, smokers, males, <75yo, and with normal renal function.) These were secondary, subgroup analyses, though do raise issues….

–one other comment: despite the above, including the first graph, I am really not fully convinced that ezetimibe has the same efficacy as statins, on an achieved LDL basis. First, the studies on statins typically show significant efficacy within 6-12 months, are usually stopped early because of this efficacy (and not go on for 6-7 years), and have diverging curves showing increasing efficacy over time. Subgroup analysis with statins usually show no differences if the patient has diabetes, is smoking, hypertensive, etc. And there was even a study in patients with ACS (the PROVE-IT TIMI 22 trial, see N Engl J Med 2004; 350:1495-1504) which looked at 4162 patients randomized to pravastatin 40mg vs atorvastatin 80mg, with initial LDL of 106 mg/dl (decreasing to 95 with pravastatin and 62 with atorvastatin), and found benefit in the atorvastatin group within 30 days and increasing benefit — diverging curves — after 2 years.

–given the multitude of data on statins, i personally think that the appropriate approach would be to first maximize the statin (ie, for those under “goal”, use at least atorvastatin 80, but would then move to rosuvastatin 40mg). If still below “goal”, would then consider adding ezetimibe (always reinforcing the appropriate lifestyle changes). Though, based on the TNT trial data above, my LDL “goal” is somewhat modified by the HDL. And we really do need more studies on ezetimibe in different populations to convince me to using it before increasing to the highest potency statin. For more blogs on statins/lipids, see here.

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