The physician outreach has begun! Pretty comprehensive and big MO explanation included
Any other docs get this in their email today? Not sure what list I was on to receive it. Possibly Medscape but not sure.
This is what was in the email
In 8179 statin-treated adults with well-controlled LDL-C (41-100 mg/dL) and CV risk factors including elevated TG (135-499 mg/dL) and either established CVD or diabetes and other CV risk factors1,2
VASCEPA® (icosapent ethyl) 4 g/d demonstrated unprecedented reductions in CV events1
Dear Dr. ----,
Results for the VASCEPA CV outcomes trial (REDUCE-IT™) have been announced and demonstrated that adding VASCEPA 4 g/d showed a 25% RRR in CV events.1
Primary endpoint:
5-POINT MACE*
Image showing key primary endpoint results from REDUCE-IT
25% RRR
NNT=21
HR=0.75
(95% CI, 0.68-0.83)
P=0.00000001
Secondary endpoint:
COMPOSITE CV DEATH, MI, STROKE
Image showing key secondary endpoint results from REDUCE-IT
26% RRR
NNT=28
HR=0.74
(95% CI, 0.65-0.83)
P=0.0000006
Hard MACE
Image showing secondary endpoint (Hard MACE) results from REDUCE-IT
CV DEATH
20% RRR
HR=0.80
(95% CI, 0.66-0.98)
P=0.03
Image showing secondary endpoint (Hard MACE) results from REDUCE-IT
MI
FATAL OR NONFATAL
31% RRR
HR=0.69
(95% CI, 0.58-0.81)
P<0.001
Image showing secondary endpoint (Hard MACE) results from REDUCE-IT
STROKE
FATAL OR NONFATAL
28% RRR
HR=0.72
(95% CI, 0.55-0.93)
P=0.01
See REDUCE-IT Results
Overall adverse event rates were similar across treatment groups
• Numerically more serious adverse events related to bleeding; overall rates were low (2.7% for VASCEPA vs 2.1% for placebo, P=0.06), with no fatal bleeding observed in either group and no significant increase in adjudicated hemorrhagic stroke or serious central nervous system or gastrointestinal bleeding
• Significantly higher rate of hospitalization for atrial fibrillation or flutter, though rates were low (3.1% for VASCEPA vs 2.1% for placebo, P=0.004)
Significant reduction in key secondary composite endpoint of CV Death, MI, and Stroke1
VASCEPA showed a 26% RRR in the key secondary endpoint, which was a composite first occurrence of CV Death, Nonfatal MI, and Nonfatal Stroke (3-point MACE).
Learn more »
VASCEPA demonstrated significant reductions in CV Death, MI, and Stroke1
Significant reductions across secondary endpoints of first occurrence of CV event:
• CV death: 20% RRR; HR=0.80 (95% CI, 0.66-0.98), P=0.03; VASCEPA (n=174), placebo (n=213)
• MI: 31% RRR; HR=0.69 (95% CI, 0.59-0.81), P<0.001; VASCEPA (n=250), placebo (n=355)
• Stroke: 28% RRR; HR=0.72 (95% CI, 0.56-0.93), P=0.01; VASCEPA (n=98), placebo (n=134)
Learn more »
FDA has not reviewed and opined on a supplemental new drug application related to REDUCE-IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population.
NNT=number needed to treat; RRR=relative risk reduction.
* 5-point MACE was defined as a composite of first occurrence of CV Death, Nonfatal MI, Nonfatal Stroke, Coronary Revascularization, and Unstable Angina Requiring Hospitalization.
References: 1. Bhatt DL, Steg PG, Miller M, et al; on behalf of the REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia [published online ahead of print November 10, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1812792. Bhatt DL. AHA 2018, Chicago. 2. Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial. Clin Cardiol. 2017;40:138-148.
FDA-Approved Indication and Limitations of Use for VASCEPA1
• VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia
• In patients with severe hypertriglyceridemia, the effect of VASCEPA on cardiovascular mortality or morbidity or on the risk of pancreatitis has not been determined
Important Safety Information for VASCEPA from FDA-Approved Label
Data from Two 12-Week Studies (MARINE and ANCHOR) of Patients with Triglycerides Values of 200 to 2000 mg/dL (n=622 on VASCEPA, n=309 on placebo)1
• VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components
• In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy
• Use with caution in patients with known hypersensitivity to fish and/or shellfish
• The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia (2.3% VASCEPA, 1.0% placebo)
• Adverse events may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088
• Patients receiving treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically
• Patients should be advised to swallow VASCEPA capsules whole; not to break open, crush, dissolve, or chew VASCEPA
Please see full Prescribing Information for more information on VASCEPA.
IMPORTANT INFORMATION FOR HCPs ABOUT VASCEPA® (ICOSAPENT ETHYL) CAPSULES
IMPORTANT NEW INFORMATION: REDUCE-IT™ CARDIOVASCULAR OUTCOMES STUDY OF VASCEPA®2*
The effects of VASCEPA on the prevention of cardiovascular events was evaluated in a multi-center, double-blind, randomized, placebo-controlled, event-driven trial (REDUCE-IT, NCT01492361) in 8,179 adult patients at low-density lipoprotein cholesterol (LDL-C) goal, with established cardiovascular disease (CVD) or at high risk for CVD, and hypertriglyceridemia (fasting triglycerides (TG) ≥135 and <500 mg/dL).
• Patients were eligible to enter the trial if they were at least 45 years of age and on stable statin therapy with fasting LDL-C levels of >40 and ≤100 mg/dL and fasting TG levels of ≥135 and <500 mg/dL. Patients also needed to have either established CVD (secondary prevention cohort), defined as documented history of coronary artery disease, cerebrovascular or carotid disease, or peripheral artery disease, or be at least 50 years of age with diabetes and at least one additional risk factor (primary prevention cohort).
- Key exclusion criteria included severe heart failure, active severe liver disease, hemoglobin A1c ≥10.0%, planned coronary intervention or surgery, history of acute or chronic pancreatitis, and known hypersensitivity to fish, shellfish, or ingredients of VASCEPA or placebo.
• 70.7% of patients were enrolled based on having established CVD (secondary prevention cohort), 29.3% were enrolled based on being at high risk for CVD (primary prevention cohort).
• Patients were randomly assigned 1:1 to receive either VASCEPA (4 grams daily) or placebo (4089 VASCEPA, 4090 placebo).
• The median follow-up duration was 58 months (4.9 years).
• Overall, 99.8% of patients were followed until the end of the trial or death.
• The median age at baseline was 64 years (range: 44 years to 92 years), with 46% being at least 65 years old; 28.8% were women.
• The trial population was 90.2% White, 1.9% Black, and 5.5% Asian; 4.2% identified as Hispanic ethnicity.
• Regarding prior diagnoses of cardiovascular disease, 46.7% had prior myocardial infarction, 6.1% prior unknown stroke or transient ischemic attack (TIA), and 9.2% had symptomatic peripheral arterial disease.
• Selected additional baseline risk factors included hypertension (86.6%), diabetes mellitus (0.7% type 1; 57.8% type 2), current daily cigarette smoking (15.2%), New York Heart Association class I or II congestive heart failure (17.7%), and eGFR < 60 mL/min per 1.73 m2 (22.2%).
• Patients enrolled were treated with statin therapy at baseline with most (93.2%) on a high- (30.8%) or moderate-intensity (62.5%) statin therapy, and 6.4% were also taking ezetimibe at baseline.
• Most patients at baseline were taking at least one other cardiovascular medication including anti-platelet agents (79.4%), beta blockers (70.7%), angiotensin converting enzyme (ACE) inhibitors (51.9%), or angiotensin receptor blockers (27.0%).
• On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was 75.0 [62.0, 89.0] mg/dL; the mean (SD) was 76.2 (20.3) mg/dL.
• On stable background lipid-lowering therapy, the median [Q1, Q3] fasting TG was 216.0 [176.0,272.5] mg/dL; the mean (SD) was 233.2 (80.1) mg/dL.
The primary results from REDUCE-IT are shown in the Table below (see CONDUCT OF REDUCE-IT AND ANALYSIS AND REVIEW OF REDUCE-IT DATA).
Effect of VASCEPA on Cardiovascular Events in Patients with Established CVD or at High Risk for CVD with Statin-treated Triglycerides ≥135 and <500 mg/dL in REDUCE-IT
VASCEPA significantly reduced the following:
• the risk for the primary composite endpoint (5-point MACE: time to first occurrence of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; p<0.001), and
• the key secondary composite endpoint (3-point MACE: time to first occurrence of cardiovascular death, myocardial infarction, or stroke; p<0.001).
Prespecified hierarchical testing of other secondary endpoints revealed significant reductions in the following:
• cardiovascular death (p=0.03),
• fatal or nonfatal myocardial infarction (p<0.001),
• fatal or nonfatal stroke (p=0.01),
• emergent or urgent coronary revascularization (p<0.001), and
• hospitalization for unstable angina (p=0.002).
The benefits of VASCEPA were seen on a background of predominately (93.2%) moderate- to high-intensity statin use and median baseline LDL-C levels of 75.0 mg/dL.
The Kaplan-Meier estimates of the cumulative incidence of the primary and key secondary composite endpoints over time are shown in Figure 1 and Figure 2 below.
Figure 1. Estimated Cumulative Incidence of Primary Composite Endpoint Over 5 Years in REDUCE-IT
Kaplan-Meier curve for the primary composite endpoint over 5 years in REDUCE-IT
CI denotes confidence interval. Curves were visually truncated at 5.7 years due to a limited number of events beyond that point in time; all patient data were included in analyses.
Figure 2. Estimated Incidence of Key Secondary Composite Endpoint Over 5 Years in REDUCE-IT
Kaplan-Meier curve for the key secondary composite endpoint over 5 years in REDUCE-IT
CI denotes confidence interval. Curves were visually truncated at 5.7 years due to a limited number of events beyond that point in time; all patient data were included in analyses.
The difference between VASCEPA and placebo in median percent change in TG from baseline to Month 4 was -20.1 (p<0.001) and from baseline to Month 12 was -19.7 (p<0.001). At Month 12, the median [Q1, Q3] TG was 175.0 [132.0, 238.0] mg/dL in the VASCEPA group, with 35.9% of patients having TG <150 mg/dL and 61.3% having a TG <200 mg/dL. The difference between VASCEPA and placebo in median percent change in LDL-C from baseline to Month 12 was -6.6% (p<0.001). At Month 12, the median [Q1, Q3] LDL-C was 77.0 [63.0, 94.0] mg/dL in the VASCEPA group, with 35.5% of patients having LDL-C <70 mg/dL and 79.9% having LDL-C <100 mg/dL.
Important Safety Information for VASCEPA from REDUCE-IT (n=4089 on VASCEPA, n=4090 on placebo)
• Patients were exposed to VASCEPA or placebo for a median of 58 months; 86.9% of patients were exposed for ≥ 12 months, 77.2% were exposed for ≥ 24 months, 64.6% were exposed for ≥ 36 months, 53.6% were exposed for ≥48 months, 29.5% were exposed for ≥ 60 months, and 0.1% were exposed for ≥72 months.
• Overall adverse event rates were similar across treatment groups.
- Adverse events and serious adverse events leading to study drug discontinuation were similar to placebo.
- The one serious adverse event that occurred at a frequency of at least 2% was pneumonia (2.6% in the VASCEPA group and 2.9% in the placebo group, P=0.42)
Treatment-Emergent Adverse Events
• Adverse events occurring in 5% of VASCEPA patients and statistically more frequently with VASCEPA than placebo (Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018, Supplementary Appendix):
- Peripheral edema (6.5% VASCEPA patients versus 5.0% placebo patients)
o There was no significant difference in the prespecified adjudicated tertiary endpoint of new congestive heart failure, which occurred in 4.1% of VASCEPA patients versus 4.3% of placebo patients.
- Constipation (5.4% VASCEPA patients versus 3.6% placebo patients)
- Atrial fibrillation (5.3% VASCEPA patients versus 3.9% placebo patients)
o This adverse event finding is consistent with an increase in the prespecified adjudicated tertiary endpoint of atrial fibrillation or flutter requiring hospitalization, which occurred in 3.1% of VASCEPA patients versus 2.1% of placebo patients (P=0.004).
- The rate of treatment-emergent serious adverse events for bleeding was 2.7% in the VASCEPA group versus 2.1% in the placebo group, with a nonsignificant, but trending p-value of 0.06
- There were
o No fatal bleeding events in either group,
o No significant increases in adjudicated hemorrhagic stroke (0.3% in VASCEPA patients versus 0.2% in placebo patients; P=0.55),
o No significant serious central nervous system bleeding (0.3% versus 0.2%; P=0.42), and
o No significant gastrointestinal bleeding (1.5% versus 1.1%; P=0.15).
Mineral oil placebo consideration and analysis
In REDUCE-IT, a placebo containing mineral oil was used to mimic the color and consistency of the drug studied. No strong evidence for biological activity of the same mineral oil was identified in connection with FDA approval of VASCEPA in July 2012 based on the MARINE phase 3 clinical trial, in connection with FDA review of the ANCHOR phase 3 clinical trial, or after several years of quarterly review by the Data Monitoring Committee (DMC) for REDUCE-IT after FDA requested that the DMC periodically assess unblinded lipid data to monitor for signals that the placebo might not be inert. While the DMC noted variation in LDL-C measurements in both arms and that a small physiological effect of mineral oil might be possible, the DMC concluded that it was not possible to determine if the LDL-C increase in the placebo arm was a natural increase over time or due to the mineral oil, they found no apparent effect on outcomes and found that this small change was unlikely to explain the observed benefit of VASCEPA over placebo.
Each of the three VASCEPA clinical trials, MARINE, ANCHOR and REDUCE-IT, was conducted under a special protocol, or SPA, agreement with FDA in which mineral oil was agreed with FDA as an acceptable placebo.
As published within the main presentation of the REDUCE-IT results (Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.), at baseline, the median LDL-C was 75.0 mg/dL. The median change in LDL-C was 3.1% (+2.0 mg/dL) for VASCEPA and 10.2% (+7.0 mg/dL) for the mineral oil placebo arm; placebo-corrected median change from baseline of -6.6% (-5.0 mg/dL; p < 0.001). If mineral oil in the placebo might have affected statin absorption in some patients, this might have contributed to differences in outcomes between the groups. However, the relatively small differences in LDL-C levels between groups would not be likely to explain the 25% risk reduction observed with VASCEPA, and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDL-C level among the patients in the placebo group. Although open label, Japan EPA Lipid Intervention Study (JELIS) previously demonstrated a 19% risk reduction without a mineral oil placebo.
CONDUCT OF REDUCE-IT AND ANALYSIS AND REVIEW OF REDUCE-IT DATA
FDA has not reviewed and opined on a supplemental new drug application related to REDUCE-IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population.*
REDUCE-IT results were first presented at the 2018 Scientific Sessions of the American Heart Association (AHA) on November 10, 2018 in Chicago, Illinois and concurrently published online in The New England Journal of Medicine (NEJM).2
REDUCE-IT was sponsored by Amarin Pharma, Inc. and its affiliates and conducted under a special protocol assessment agreement with FDA.
• The REDUCE-IT steering committee, consisting of academic physicians, and Amarin representatives developed the protocol (Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018.) and were responsible for the conduct and oversight of the study, and data interpretation.
• The primary, secondary, and tertiary adjudicated endpoint analyses were validated by the data monitoring committee independent statistician.
Further REDUCE-IT data assessment and data release could yield additional useful information to inform greater understanding of the trial outcome:
• Further detailed data assessment by Amarin and regulatory authorities will continue and take several months to complete and record
• The final evaluation of the totality of the efficacy and safety data from REDUCE-IT may include some or all of the following, as well as other considerations:
• New information affecting the degree of treatment benefit on studied endpoints
• Study conduct and data robustness, quality, integrity and consistency
• Additional safety data considerations and risk/benefit considerations
• Consideration of REDUCE-IT results in the context of other clinical studies
VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) and certain commercial plans to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population. We encourage you to check that for yourself.
IMPORTANT INFORMATION FOR HCPs ABOUT CONTINUED UNCERTAINTY AROUND THE BENEFIT, IF ANY, OF LOWERING TG LEVELS AFTER STATIN THERAPY IN PATIENTS WITH HIGH (200-499 mg/dL) TG LEVELS
• In REDUCE-IT, cardiovascular benefits appeared similar across baseline levels of triglycerides (less than 150 mg/dL, 150 to 199 mg/dL, and 200 mg/dL or greater).
- Additionally, the reduction in major adverse cardiovascular events with VASCEPA appeared to occur irrespective of an achieved triglyceride level above or below 150 mg/dL at one year, suggesting that the cardiovascular risk reduction was not tied to achieving a more normal triglyceride level.
- These observations suggest that at least some of the impact of VASCEPA on the reduction in ischemic events may be explained by metabolic effects other than triglyceride lowering.
• VASCEPA is not FDA-approved to lower TG levels in statin-treated patients with mixed dyslipidemia and persistent high (≥200 mg/dL and <500 mg/dL) TG levels due to current uncertainty regarding the benefit, if any, of drug-induced changes in lipid/lipoprotein parameters beyond statin-lowered LDL-C on cardiovascular risk among statin-treated patients with residually high TG.
- Other cardiovascular outcomes trials (ACCORD Lipid, AIM-HIGH, and HPS2-THRIVE), while not designed to test the effect of lowering TG levels in patients with high TG levels after statin therapy, each failed to demonstrate incremental cardiovascular benefit of adding a second lipid-altering drug (fenofibrate or formulations of niacin), despite raising HDL-C and reducing TG levels, among statin-treated patients with well-controlled LDL-C.
Other cardiovascular outcomes trials that studied fish oil or mixtures of omega-3 acids that include the omega-3 acid, DHA, have reported negligible impact on cardiovascular events.
No head-to head, randomized, well-controlled studies have been conducted to compare the effects of VASCEPA with other FDA-approved TG-lowering therapies.
POTENTIAL MECHANISMS OF ACTION
Mechanisms responsible for the benefit shown in REDUCE-IT were not the focus of REDUCE-IT, but the banked samples and array of biomarkers measured leave room for mechanistic insights through future analyses. Potential mechanisms discussed in Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018., include TG reduction, anti-thrombotic effects, anti-platelet or anticoagulant effects, membrane-stabilizing effects, effects on stabilization and/or regression of coronary plaque and inflammation reduction. More study is needed to determine to what extent, if any, these effects or others may be responsible for the CV risk reduction benefit demonstrated with use of VASCEPA in REDUCE-IT.
*This information is intended to ensure Amarin meets its continuing obligation to update healthcare professionals regarding off-label use of VASCEPA to assure that its communications remain truthful and non-misleading, consistent with the federal court approved settlement under Amarin Pharma, Inc. et al. v. United States Food and Drug Administration et al., 119 F.Supp.3d 196, 236 (S.D.N.Y. 2015).
Disclosure References: 1. VASCEPA [package insert]. Bedminster, NJ: Amarin Pharma, Inc.; 2017. 2. Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018. Bhatt DL, AHA 2018, Chicago.
