In this episode we discuss two articles about high cholesterol, one dealing with new targets for treatment, and one about the PCSK9 inhibitors.

Presenters: Nam Ha, MD and Britney Plotnick, MD, Wellspan York Hospital Internal Medicine Residency Program
Hosts: Giselle Aerni, MD and Sonya Del Tredici, MD
Producer: Robert Stuntz, MD

Article 1: A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. Amarenco, Pierre MD; Kim, Jong MD et al., N Engl J Med 2020; 382:9-19.

Background

After an ischemic stroke of atherosclerotic origin or TIA, guidelines recommend intensive statin therapy to lower serum lipid levels. The SPARCL trial (2006 by the same author) showed a reduction in recurrent stroke with atorvastatin compared to placebo in patients with stroke, and forms the basis for this recommendation. However, a subsequent analysis of the data from that trial showed patients with LDL < 70 had a 28% lower relative risk reduction of stroke than those with LDL < 100 mg/dL. The current guideline recommends a high intensity statin, but does not specify the LDL target. There are limited data on whether a target LDL of 70 is better than a target LDL of 100. Thus, the Treat Stroke to Target trial (TST) was done.

What is the clinical question?

Population: 3/2010–12/2018, Adults from France and South Korea, ischemic stroke in prior 3 months or TIA within prior 15 days (modified Rankin 0-3), confirmed with imaging. Some patients were on anticoagulation, but the reason was not given.

Intervention: Any type and any dose of statin to reach the target of LDL < 70 mg.dL or LDL 90-110 mg/dL. Ezetimibe was also added throughout the follow-up to maintain target. Other interventions also include blood pressure control (target 130/80 in diabetes; less than 140/90 otherwise), hemoglobin A1c%<7, and encouraging smoking cessation.

Comparison: Lower target group versus higher target group.

Outcomes: Primary endpoints: Nonfatal cerebral infarction or stroke of undetermined origin, nonfatal myocardial infarction, hospitalization for unstable angina followed by urgent coronary revascularization, TIA with urgent carotid revascularization, cardiovascular death (including unexplained sudden death).
Secondary endpoints: MI, urgent coronary revascularization after onset of new symptoms, cerebral infarct or urgent revascularization of carotid or cerebral artery after TIA, cerebral infarction with TIA, urgent or elective revascularization of coronary, cerebral, peripheral artery, CVS death, death from any cause, intracranial hemorrhage, newly diagnosed diabetes.

Is the trial valid?

Randomized? yes

Blinded? Blinded adjudicators of events that are components of end points

Groups similar at baseline? yes, (although a higher percentage of patients in the lower target group were receiving ezetimibe than the higher target one)

Follow-up sufficiently long and complete? Maybe. First follow-up was 3 weeks after randomization to adjust medication dose. Follow-up every 6 months after that with measurement of LDL and readjustment of medication as needed. Median follow-up is 5.3 years for French patients vs 2 years for Korean patients (SK patients recruited much later in the trial). Study stopped short due to sponsors lacking funds. Longer follow-up would help see a better picture (e.g. increased incidence of intracranial hemorrhage with LDL target < 70?).

Intention to treat analysis? Yes

Were there enough patients? There were 3760 patients per protocol, but 2873 patients eventually randomized; this may reduce validity of results.

Funding bias? Maybe. Study was funded by Pfizer, AstraZeneca, and Merk. Authors received fees.

What are the results?

Sample size: 2873 patients; 2860 included.

Treatment effects: primary endpoint 8.5% in the lower-target (2.27 per 100 person-years) vs 10.9% in the higher-target (2.98 per 100 person-years). Adjusted hazard ratio, 0.78; 95% CI; 0.61-0.98; P=0.04.

NNT = 42 for the follow-up interval

Adverse events: Intracranial hemorrhage 18 patients (1.3%) in lower-target vs 13 patients (0.9%) in higher-target. Hazard ratio 1.38, 95% CI, 0.68-2.82. New diabetes in 103 patients (7.2%) in lower-target vs 82 (5.7%) in higher-target. Hazard ratio 1.27; 95% CI, 0.95-1.70.

Will the results help me in patient care?

Perhaps…in the future. It is good to keep in mind that keeping a lower target LDL is shown here to prevent more cardiovascular events, although the confidence intervals have not been adjusted for multiple comparisons in the trial. Patients, recruited in the FOURIER trial where there was addition of PCSK9 inhibitor for patients with persistent LDL > 70 despite of being on high-dose statin, have LDL level around 30 mg/dL in the intervention group, and these patients have a reduction in major cardiovascular events (including stroke and cardiovascular death).

Secondary endpoints such as intracranial hemorrhage could not be statistically analyzed due to hierarchical testing. Perhaps we need more studies to see whether stricter control of LDL can be associated with increased risk of intracranial bleed before making a final determination.

Patients included have Rankin score from 0-3; what about 4-5?

(Rankin Score: 0 = no symptoms, 1 = no disability, 2-3 = need help with daily activities, 4-5 = dependent or bedridden, and 6 = death)

References

Amarenco, Pierre MD; Kim, Jong MD et al., A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. N Engl J Med 2020; 382:9-19

JAMA Users Guide article for reference: II How to Use An Article About Therapy or Prevention

Amarenco et al. High Dose Atorvastatin after Stroke or Transient Ischemic Attack. N Engl J Med 2006; 355:549-559

Sabatine, Marc MD et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017; 376:1713-1722

SPARCL Investigators. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack. N Engl J Med 2006; 355:549-559

Article 2: Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. By GG Schwartz, et. al. N Eng J Med 2018; 379: 2097-2107. (Odyssey Trial)

Why is this study important?

Patients who have had ACS are at a high risk for recurrent ischemic cardiovascular events. Patients who receive statins to lower LDL have a lower risk. PCSK9 helps to degrade LDL receptors, decreasing the clearance of LDL from the circulation. Hence, monoclonal antibodies to PCSK9 were developed to reduce LDL cholesterol. Prior to this study, it was unknown if PCSK9 decreases cardiovascular risk after ACS. ACS is fairly common in my outpatient practice, so I was interested in learning further medical treatment to reduce cardiovascular events.

What is the clinical question?

Does alirocumab, a PCSK9 monoclonal antibody, reduce the risk of recurrent ischemic cardiovascular events among patients who had an ACS within the prior 1-12 months and in whom lipid levels exceed specified thresholds despite high intensity or maximum dose tolerated statin therapy? To put it simply, does alirocumab improve cardiovascular outcomes after an ACS in patients receiving high intensity statin?

Population: ≥ 40 yo, hospitalized for ACS (MI or UA) 1-12 months prior, with LDL ≥ 70 mg/dL, non-HLD ≥ 100 mg/dL, or an apolipoprotein B level of ≥ 80. Lipid levels needed to be stable for a minimum of 2 weeks with atorvastatin (40-80mg), rosuvastatin (20-40mg), or the maximum tolerated dose.
Demographics: ACS: MI (83%), UA (16.8%). Most patients were receiving guideline-recommended medications & had a coronary revascularization. Mean LDL: baseline was 92 +/- 31 mg/dL. At the time of randomization, 88.8% of patients were receiving atorvastatin 40-80mg or rosuvastatin 20-40mg daily.

Intervention: Alirocumab 75mg subQ every 2 weeks. Target LDL 25-50mg/dL (avoided LDL < 15mg/dL)-> Alirocumab was adjusted every 2 weeks

Control: Placebo

Outcomes: Primary endpoints: Death from CHD, Nonfatal MI, fatal or nonfatal ischemic stroke, or UA requiring hospitalization.
Secondary endpoints: CHD event (Primary endpoint), ischemia driven coronary revascularization procedure, & hospitalization for CHF

Is the study valid?

Randomized? Yes

Multi-center? 57 countries, 1315 sites

Blinded? Yes, double-blind

Were the groups similar at the start of the trial? Yes

Was the sample size large enough? Yes, with 18924 participants

Were all the participants accounted for at the end of the study? Yes.

Premature discontinuation for reasons other than death: Alirocumab discontinued: 1343 (14.2%) Placebo discontinued: 1496 (15.8%)

Was the follow up long enough? Yes, patients were followed for 2.3-3.4 years (median 2.8 years).

Was the statistical analysis appropriate? yes

Is the hypothesis biologically plausible? yes

What are the results?

Alirocumab + statins lowered LDL more than statins alone. At month 48, mean LDL = 66 mg/dL in the alirocumab group, and 103 mg/dL in the placebo group. Note that the alirocumab group includes values measured after discontinuation of alirocumab & after blinded substitution of placebo for alirocumab.

The composite primary endpoint was lower in the alirocuman group thatn th eplacebo group (9.5% vs. 11.1%).

The secondary endpoints were lower in the alirocumab group than the placebo group.

Number needed to treat? 62.5 needed to treat to prevent the occurrence in the primary endpoint in 2.8 years, or 49 patients would need to be treated for 4 years to prevent the occurrence of 1 primary endpoint.

Are the results precise? Yes, except for death from CHD

Are the results statistically significant? Yes, except for death from CHD

Are the results clinically significant? Yes

Were there adverse events reported? Similar except local injection site reactions were more common in alirocumab (3.8%) than placebo (2.1%).

Summary of results: In patients who had ACS and with lipid levels exceeding threshold while on high intensity or maximum tolerated statin dose, the risk of death from CHD, non-fatal MI, fatal or non-fatal ischemic stroke, or UA requiring hospitalization, was lower among those who were treated with alirocumab than with placebo. The benefit was more pronounced in patients who had a baseline LDL of 100 or more.

How will these results help us in patient care?

Are the patients in the study similar to your patients? For the most part, although there are more Asians in this study than I see in my practice.

Is the intervention in the study feasible in your practice setting? There are patients who are on statins who do not get an optimal LDL of 70. I believe over time, this medication will be used in my practice.

Limitations: Alirocumab is very expensive (a few thousand dollars) and long-term side effects are unclear. Alirocumab is injectable, which can be a problem for some.

Future clinical trials: There are some patients who are intolerant of statin. Can alirocumab be prescribed for these patients?

What are the benefits and harms of t