EBM Lecture Handout #5: Heparin in ACS

It is often good to review why we do what we do. Heparin is a therapy that is started multiple times every day in every emergency department in the world. It is our bread and butter. But what exactly does heparin do? Specifically:

What is the benefit for our patients of giving heparin in the setting of an acute coronary syndrome?

There are 7 major studies that compared heparin to placebo in ACS:

1) Théroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319:(17)1105-11. PMID: 3050522

• Prospective RCT, 479 patients admitted to CCU
• All patients had ECG changes
• 4 arms: ASA+placebo, ASA+heparin, heparin+placebo, placebo+placebo
• In one of multiple comparators (MI), heparin outperformed placebo – but those patients did not receive ASA
• In patients treated with ASA (like all current patients), heparin had no effect
• ASA plus heparin doubled serious bleeding compared to ASA, heparin alone, or placebo

Bottom line: In patients treated with ASA, heparin showed no benefit, but increased bleeding

2) RISC trial: Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet. 1990;336:(8719)827-30. PMID: 1976875

• Prospective RCT of 796 men with unstable angina or non-Q-wave MI
• 4 arms: ASA+placebo, ASA+heparin, heparin+placebo, placebo+placebo
• At 90 days there was no difference in death or MI with heparin
• When looking at secondary outcomes, they noted a decrease in MIs while on heparin at day 6, but there was a rebound effect where the numbers equalized as soon as the heparin was stopped

Bottom line: Again, there was no benefit from heparin

3) Cohen M, Adams PC, Hawkins L, Bach M, Fuster V. Usefulness of antithrombotic therapy in resting angina pectoris or non-Q-wave myocardial infarction in preventing death and myocardial infarction (a pilot study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group). Am J Cardiol. 1990;66:(19)1287-92. PMID: 2244556

• RCT of 93 patients with unstable angina or non-Q-wave MIs
• ASA vs heparin/warfarin vs ASA and heparin/warfarin
• Significantly underpowered, but ASA alone group looked better on raw numbers

Bottom line: No benefit of the combination of heparin and warfarin

4) Holdright D, Patel D, Cunningham D, et al. Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina. J Am Coll Cardiol. 1994;24:(1)39-45. PMID: 8006281

• Prospective RCT of 285 patients with unstable angina
• ASA+placebo versus ASA+heparin
• No differences in any outcomes

Bottom line: Noticing a trend? No benefit of adding heparin to ASA

5) Cohen M, Adams PC, Parry G, et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation. 1994;89:(1)81-8. PMID: 8281698

• RCT of 214 patients with unstable angina or non-Q-wave MIs
• ASA  alone vs ASA plus heparin followed by 3 months of warfarin (presumably, looking to counter the rebound effect)
• No statistical significance in primary outcome of recurrent angina/MI/death at 3 months (warfarin group was better in raw numbers – 19% vs 28%)
• There was a difference in the composite outcome at 14 days 10.5% versus 27% p=0.004
• Unfortunately, they did not follow these patients after the warfarin was stopped to see if the rebound occurred later

Bottom line: No statistical difference in the primary outcome. Again, there were some measurable changes early on.

6) Gurfinkel EP, Manos EJ, Mejaíl RI, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol. 1995;26:(2)313-8. PMID: 7608429

• RCT of 219 patients with unstable angina
• ASA vs ASA + heparin vs ASA + LMWH
• Only followed the patients while they were inpatients up to 7 days
• No difference between ASA + heparin versus ASA alone except increased bleeding
• LMWH did have a decrease in MI/recurrent ischemia over the short term (no long term follow up)

Bottom line: Unfortunately, no long term follow up, but in the first week the LMWH did decrease MIs. If they had followed their patients beyond one week, would they have seen the same rebound effect as in every other study?

7) FRISC trial: Gurfinkel EP, Manos EJ, Mejaíl RI, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol. 1995;26:(2)313-8. PMID: 8596317

• RCT of 1506 patients with unstable angina or non-Q-wave MI. (They had to have ST depression or T wave inversion. Unstable angina was a different entity back in the day.)
• Fragmin for 45 days versus placebo (everyone gets ASA)
• The had 98% follow up at 150 days, and there was no benefit of Fragmin therapy
• However, presumably because it was an industry sponsored study, and based on the earlier trials that showed benefit early and no benefit late, they chose 6 days as their primary outcome
• At 6 days, Fragmin decreased MI by 6% (p=0.04). So if your patient cares only about what happens to them at 6 days, and not at a month or longer, dalteparin may be a good choice

Bottom line: There were no difference at 150 day follow up between the groups, but the primary outcomes of 6 days showed a decrease in MIs.

What does the Cochrane review say?

Andrade-Castellanos CA, Colunga-Lozano LE, Delgado-Figueroa N, Magee K. Heparin versus placebo for non-ST elevation acute coronary syndromes. Cochrane Database Syst Rev. 2014;6:CD003462. PMID: 24972265

• No change in mortality
• Decrease MI RR=0.40 95% CI 0.25-0.63
• However, this decrease is almost entirely driven by the largest study – FRISC; they used the 6 day outcome, because that was the primary outcome, however we know that there was no difference at 150 days.

Summary

We know heparin has never demonstrated a mortality benefit, so you are not giving it so save your patient’s life.

Taken as a whole, this literature seems to illustrate that heparin has a physiologic effect that can be demonstrated early after an MI. In the first few days of therapy, the number of non-fatal MIs is decreased. The importance of a non-fatal MI (aka an increased lab test) is a good question, but it turns out to be irrelevant here, because as soon as the heparin stops, there is a rebound effect and all benefit is lost. In terms of patient oriented outcomes, there is clearly no benefit at one month from giving heparin.

The major caveat is that all of these studies were done in a pre-catheterization era. One could theorize that a stent might prevent the rebound we are seeing when heparin is stopped. Maybe this is a good bridge to intervention.

However, we have to recognize that this is just a theory. There is no science to back up this claim. Also, we should examine the outcomes we are changing. There is no change in mortality. We can decrease non-fatal MIs by about 3%. If you could somehow hold on to that benefit with PCI, we still have to recognize that this is balanced by the approximately 3-4% increase in major bleeding that we know accompanies heparin use. So even in this theoretical world, heparin is not clearly beneficial.

My most important take home point: Heparin is often started on patients without any informed choice or shared decision making process. It is started because “this is an MI, and we need to treat it.” However, we should recognize that any medication that does not clearly save lives cannot just be started without a patient’s consent.

I would tell my patients: “We have this medicine, called heparin, that has traditionally been given to all patients with a heart attack. It will not change whether you live or die. It decreases heart attacks in the first week, but by one month there is no benefit to this medicine. The major side effect of this medicine is that about 1 in 33 people will have a problem with major bleeding, such as vomiting blood, bleeding in the brain, or requiring blood transfusions.”

Want more information?

For a review by some of emergency medicine’s finest minds, see the fantastic NNT site:

http://www.thennt.com/nnt/heparin-for-acute-coronary-syndromes/

For a more eloqent review of these same studies than I can provide, check out the Pulmonary Intensivist’s Blog: Mythbusting: Heparin isn’t beneficial for noninvasive management of NSTEMI

For those of you with EM:RAP subscriptions, this was also discussed a few years back: https://www.emrap.org/episode/2012/june/minijournalclub1