Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes: Difference between revisions

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Revision as of 04:08, 19 September 2013

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Objective

To study the effects of intravenous recombinant Apo A-1 Milano/phospholipid complexes (ETC-216) on arterial plaque burden in patients with acute coronary syndromes (ACS).^[1]

Previous studies conducted on mice and rabbits showed that rApo A-I Milano/phospholipid complex can mobilize cholesterol within 48 hours and reduce atherosclerosis.^[1]

Timeline

Start Date

November 2001

End Date

March 2003

Methods

A 5 week, randomized, double-blinded, multicenter, parallel-treatment randomized control trial^[1]
Patients enrolled: 123 patients
Patients randomly assigned: 57 patients

Inclusion Criteria

Age: 30-75 years
Angiography performed within 14 days following ACS event.
At least 20% luminal diameter stenosis by visual estimated required
Intravascular ultrasound (IVUS) done within 14 days of ACS event.
No more than 50% luminal narrowing in a segment that is at least 30 mm in length.
No previous percutaneous coronary intervention (PCI)
Other anti-lipidemic drugs permitted during the study as long as no introduction or new medication or change in dosage occurs within 6 weeks of study start or end date.

Study Arms

11 patients in placebo group consisting of 0.9% normal saline
21 patients in low (15 mg/kg) dose ETC-216 group
15 patients in high (45 mg/kg) dose ETC-216 group

The ratio of patient enrollment in the 3 groups was 1:2:2, respectively.^[1]

IVUS was done at baseline. Intravenous infusion took place weekly for 5 consecutive weeks. Two weeks after infusion, IVUS was repeated for comparison.^[1]

Outcomes

Primary Outcome

Change in percent atheroma volume as measured by IVUS^[1]

Secondary Outcome

Assessment of adverse events, quantitative angiographic changes, change in average maximal thickness or in total volume of atheroma,or atheroma volume change in most and least severely diseases 10-mm-long segments.^[1]

Results

10 patients were discontinued, while another 3 elected to discontinue
2 patients were withdrawn for adverse events
5 had IVUS that could not be analyzed

There was a significant difference in atheroma volume, mean change in total atheroma volume and thickness in the ETC-216 groups (combined) showing a 3.17% difference (p=0.02, p<0.001, p<0.001 respectively).^[1] This statistical significance was not seen in patients on placebo. Most regression using ETC-216 was seen in subsegments of 10 mm long that are severely diseased, in comparison to those with only mild disease (p<0.001).^[1]

However, luminal diameter on angiography was not different when comparing follow-up to baseline or when comparing ETC-216 vs. placebo.^[1]

Adverse events included mainly minor gastrointestinal events, headaches,arthralgias, and edema that were found in all 3 groups. Two important adverse events that required withdrawal were:

1 patient with elevated liver function tests 3 times the upper normal limit with nausea vomiting, and cholelithiasis.^[1]
1 patient with chills, rigors, rash, nausea, vomiting, and diaphoresis that occurred during infusion.^[1]

Results

Treatment with ETC-216 (in both doses) resulted in a significant decrease in mean percentage of coronary artery volume occupied by atheroma as well as the total atheroma volume.^[1] Whereas the placebo group did not show any significant change.^[1]

Conclusion

Although Apo A-1 Milano infusions resulted in a decrease in plaque burden, further study is required to assess efficacy, safety and cost-effectiveness.^[1]

References

↑ ^1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 ^1.11 ^1.12 ^1.13 ^1.14 Nissen SE, Tsunoda T, Tuzcu EM; et al. (2003). "Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial". JAMA : the Journal of the American Medical Association. 290 (17): 2292–300. doi:10.1001/jama.290.17.2292. PMID 14600188. Unknown parameter |month= ignored (help)

[pmid14600188-1] 1.00 ^1.01 ^1.02 ^1.03 ^1.04 ^1.05 ^1.06 ^1.07 ^1.08 ^1.09 ^1.10 ^1.11 ^1.12 ^1.13 ^1.14 Nissen SE, Tsunoda T, Tuzcu EM; et al. (2003). "Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial". JAMA : the Journal of the American Medical Association. 290 (17): 2292–300. doi:10.1001/jama.290.17.2292. PMID 14600188. Unknown parameter |month= ignored (help)

[1]

@@ Line 4: / Line 4: @@
 {{CMG}}
 ==Objective==
-To study the effects of Apo A-1 Milano on arterial plaque burden.
+*To study the effects of intravenous recombinant Apo A-1 Milano/[[phospholipid]] complexes (ETC-216) on arterial plaque burden in patients with [[acute coronary syndromes]] ([[ACS]]).<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+*Previous studies conducted on mice and rabbits showed that rApo A-I Milano/phospholipid complex can mobilize cholesterol within 48 hours and reduce atherosclerosis.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+==Timeline==
+===Start Date===
+November 2001
+===End Date===
+March 2003
 ==Methods==
-Apo A-1 was infused in cholesterol fed rabbits and showed a decreased intimal thickness and macrophage content after balloon injury in [[femoral artery|femoral]] and iliac arteries. Based on these results, another pilot trial was designed using recombinant Apo A-1 Milano phospholipid complex (ETC-216) in 57 patients within two weeks of the onset of [[acute coronary syndrome]]. Subjects were randomly assigned to treatment with either ETC 216 infusion at 15 mg/kg or 45 mg/kg or to placebo. [[IVUS]] was performed at baseline and repeated at the completion of the study.
+*A 5 week, randomized, double-blinded, multicenter, parallel-treatment [[randomized control trial]]<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+*Patients enrolled: 123 patients
+*Patients randomly assigned: 57 patients
+===Inclusion Criteria===
+*Age: 30-75 years
+*[[Angiography performed]] within 14 days following [[ACS]] event.
+*At least 20% luminal diameter stenosis by visual estimated required
+*[[Intravascular ultrasound]] ([[IVUS]]) done within 14 days of ACS event.
+*No more than 50% luminal narrowing in a segment that is at least 30 mm in length.
+* No previous [[percutaneous coronary intervention]] (PCI)
+*Other [[anti-lipidemic drugs]] permitted during the study as long as no introduction or new medication or change in dosage occurs within 6 weeks of study start or end date.
+===Study Arms===
+*11 patients in placebo group consisting of 0.9% normal saline
+*21 patients in low (15 mg/kg) dose ETC-216 group
+*15 patients in high (45 mg/kg) dose ETC-216 group
+The ratio of patient enrollment in the 3 groups was 1:2:2, respectively.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+IVUS was done at baseline.  [[Intravenous infusion]] took place weekly for 5 consecutive weeks.  Two weeks after infusion, [[IVUS]] was repeated for comparison.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+===Outcomes===
+====Primary Outcome====
+Change in percent [[atheroma]] volume as measured by [[IVUS]]<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+====Secondary Outcome====
+Assessment of [[adverse events]], quantitative angiographic changes, change in average maximal thickness or in total volume of atheroma,or atheroma volume change in most and least severely diseases 10-mm-long segments.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
 ==Results==
-Treatment with ETC-216 (in both doses) resulted in a significant decrease in mean percentage of coronary artery volume occupied by atheroma as well as the total atheroma volume. Whereas the placebo group did not show any significant change.
+*10 patients were discontinued, while another 3 elected to discontinue
+*2 patients were withdrawn for adverse events
+*5 had IVUS that could not be analyzed
+There was a significant difference in atheroma volume, mean change in total atheroma volume and thickness in the ETC-216 groups (combined) showing a 3.17% difference (p=0.02, p<0.001, p<0.001  respectively).<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref> This statistical significance was not seen in patients on placebo. Most regression using ETC-216 was seen in subsegments of 10 mm long that are severely diseased, in comparison to those with only mild disease (p<0.001).<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+However, luminal diameter on angiography was not different when comparing follow-up to baseline or when comparing ETC-216 vs. placebo.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+Adverse events included mainly minor gastrointestinal events, [[headaches]],[[arthralgias]], and [[edema]] that were found in all 3 groups.
+Two important adverse events that required withdrawal were:
+*1 patient with elevated [[liver function tests]] 3 times the upper normal limit with nausea vomiting, and cholelithiasis.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+*1 patient with chills, rigors, rash, nausea, vomiting, and [[diaphoresis]] that occurred during infusion.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
+==Results==
+Treatment with ETC-216 (in both doses) resulted in a significant decrease in mean percentage of coronary artery volume occupied by [[atheroma]] as well as the total [[atheroma]] volume.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref> Whereas the placebo group did not show any significant change.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>
 ==Conclusion==
 Although Apo A-1 Milano infusions resulted in a decrease in plaque burden, further study is required to assess efficacy, safety and cost-effectiveness.<ref name="pmid14600188">{{cite journal |author=Nissen SE, Tsunoda T, Tuzcu EM, ''et al.'' |title=Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial |journal=[[JAMA : the Journal of the American Medical Association]] |volume=290 |issue=17 |pages=2292–300 |year=2003 |month=November |pmid=14600188 |doi=10.1001/jama.290.17.2292 |url=}}</ref>

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Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes: Difference between revisions

Revision as of 04:08, 19 September 2013

Objective

Timeline

Start Date

End Date

Methods

Inclusion Criteria

Study Arms

Outcomes

Primary Outcome

Secondary Outcome

Results

Results

Conclusion

References

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