Heparin in STEMI and PCI – does it help?

It’s time for another deep dive into the medical literature, this time looking at the evidence for heparin (or any anticoagulant) in the setting of STEMI and PCI. I have previously outlined the evidence that indicates that heparin shouldn’t be used (is harmful) in unstable angina and NSTEMI. However, that post did not address the role of heparin in STEMI, or in conjunction with PCI. 

In fact, when discussing this issue over the years, I have always explicitly left STEMI out of the discussion, because I had been told that anticoagulation is absolutely necessary for all patients going to the cath lab. With no reason to believe otherwise, I accepted that dogmatic teaching. Physiologically, it made sense. I could rationalize it based on the small early benefit seen in the (otherwise completely negative) heparin for NSTEMI trials. However, it has always sort of bothered me, because it is one of those recommendations that was never accompanied by a citation.

After more than a year buried in cardiology journals, I now know why: there is no evidence. Or at least nothing definitive. The AHA guidelines say we should be giving heparin to patients undergoing revascularization or receiving fibrinolytics, however all their recommendations are evidence level C, which translates to “only consensus opinion of experts, case studies, or standard-of-care”. (Antman 2004) In other words, we really don’t know.

The topic gets a bit complicated. There are a number of different anticoagulants used, in many different combinations. ACS management varies wildly from trial to trial. Some patients receive PCI while other get lytics (with varying degrees of follow-up interventions). Aspirin was used in isolation in older trials (in varying doses), while dual antiplatelet therapy is relatively routine in newer trials. Consequently, the trials cannot simply be combined to produce an easy answer.

There is no perfect trial. The complexity of the data means the conclusion of this post will be “I don’t know”. However, I learned a lot going through these studies. I think everyone (including our patients) will benefit from a better understanding of the evidence underlying the current recommendations to use heparin in STEMI and in patients undergoing revascularization, so I will attempt to summarize it succinctly in this post. 

(For the evidence in NSTEMI and unstable angina, see this post.)

Does heparin (or any anticoagulation) improve outcomes in STEMI patients undergoing PCI?

This is probably the single most important question, as PCI is the undoubted standard of care in STEMI (although, I believe thrombolytics are still more widely used worldwide). Despite the importance of the question, the unfortunate answer is: we don’t know. I am sorry, but that is the best answer I can give you. It has never really been studied.

To quote the AHA, “when primary PCI is chosen as the route of reperfusion, weight-adjusted boluses of heparin of 70 to 100 U/kg are recommended. This recommendation does not come specifically from empirical data in the setting of STEMI…” (Antman 2004) The newer version makes the same recommendation, still as a “level C”, but doesn’t mention the underlying evidence at all. (O’Gara 2013) Or if you prefer the European Society of Cardiology, “there has been no placebo-controlled trial evaluating UFH in primary PCI, but there is a large body of experience with this agent.” (Ibanez 2018) In other words, we give this medication to a lot of patients, but we have no idea if it helps or hurts.

The AHA does reference a couple of studies to make the claim that a higher activated clotting time is associated with a lower rate of complications. However, the trials they cite are unconvincing. Granger (1996) is a secondary analysis of GUSTO-I, which was a lytics trial, and so not directly relevant to the issue of anticoagulation use in PCI. Nairns (1996) is a case control study looking at 62 patients undergoing elective PCI for stable CAD (again not directly applicable to STEMI) who had a post-procedure vessel closure, comparing them to 124 who didn’t, and found that ACT times were higher in the patients without vessel closure. That is a pretty low level of evidence. 

We have better evidence in the form of the CIAO trial, discussed in more detail below, which is a 700 person RCT comparing heparin to placebo in PCI and demonstrating better outcomes with placebo. (Stabile 2008)

Of note, although the ESC does recommend heparin during the PCI procedure (without any good evidence), they do state that “routine post-procedural anticoagulant therapy is not indicated after primary PCI”. (Ibanez 2018) So they are suggesting that STEMI patients don’t need heparin in general – only during PCI.

Strangely, neither document mentions or cites the CREATE trial, a 2005 placebo controlled RCT of the low molecular weight heparin (LMWH) reviparin in STEMI, which did include some PCI patients. (Yusuf 2005) That study is discussed further in thrombolytics section below.

Bottom line: Heparin has never really been compared to placebo in STEMI patients undergoing PCI. We have no idea if it helps or harms.

Does heparin improve outcomes in STEMI patients treated with fibrinolytics?

When reading about heparin in the context of fibrinolytics, there is a lot of physiology thrown around. Older, nonspecific lytics like urokinase and streptokinase are anticoagulants by themselves, and so heparin may not be required. On the other hand, streptokinase has procoagulant potential, so it might need anticoagulation more than other lytics. The newer agents, like alteplase, have less effect on systemic coagulation factors, and may also be procoagulant. I find this theory mostly unhelpful. In many papers, it is used to explain unexpected results, and justify treatment at odds with the results of the trials. In fact, the complexity of the coagulation system makes empiric data even more important. Luckily, in the context of lytics, there are actually a few trials.

GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. Lancet. 1990; 336(8707):65-71. [pubmed]

This is a 2×2 trial design, where 12,490 MI patients were randomized to either alteplase or streptokinase, and also to either subcutaneous heparin (12,500 units BID) or no heparin. Focusing on heparin, there was no difference in the composite primary outcome (death plus severe left ventricular damage; 22.7% vs 22.9%). Major bleeding was increased with heparin (1.0% vs 0.6%; RR 1.64, 95% Cl 1.09-2.45).

High risk bleeding patients were excluded (because this is a thrombolysis trial), which would tend to minimize bleeding risks. This trial was not placebo controlled, which would usually bias in favour of the heparin group.

Bottom line: Heparin was net harmful in this trial.

ISIS-3: In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin. The International Study Group. Lancet. 1990; 336(8707):71-5. [pubmed]

Once GISSI-2 was underway, they decided to look specifically at mortality, rather than the composite endpoint, and so created this larger trial to increase their power. This is the same 2×2 trial design, where 20,891 MI patients (12,000 were the same patients as GISSI-2) were randomized to either alteplase or streptokinase, and also to either subcutaneous heparin (12,500 units BID) or no heparin. Focusing on heparin, there was no difference in mortality or cardiac complications at 30 days. There was a small increase (0.5% vs 1.0%) in major bleeding with heparin (RR 1.79; 95% CI 1.31-2.45). Again, this trial was not placebo controlled, which would usually bias in favour of the heparin group.

Bottom line: Heparin was net harmful in this trial.

FRAMI: Kontny F, Dale J, Abildgaard U, Pedersen TR. Randomized trial of low molecular weight heparin (dalteparin) in prevention of left ventricular thrombus formation and arterial embolism after acute anterior myocardial infarction: the Fragmin in Acute Myocardial Infarction (FRAMI) Study. Journal of the American College of Cardiology. 1997; 30(4):962-9. [pubmed] [free full text]

This is a multicenter, double-blind RCT that compared dalteparin (150 IU/kg subQ BID) to placebo in 517 MI patients after streptokinase. (The original sample size was 776. Significantly more patients left the trial in the dalteparin group. 33 patients were excluded for hemorrhage as compared to only 3 in the placebo group.) The primary outcome – a combination of left ventricular thrombus and arterial embolism – was lower in the dalteparin group (21.9% vs 14.2%, p=0.03). However, all of the arterial emboli occurred in the dalterpain group, so the entire difference was from the nonpatient oriented “LV thrombus”. Stroke was unchanged (1.3% vs 1.0%). Reinfarction was also the same in both groups (2.1% vs 1.6%) and mortality was also unchanged (5.9% in both groups). Major hemorrhage was higher in the dalteparin group (2.9% versus 0.3%, p=0.006). 

Bottom line: Although the primary outcome was positive, for all the outcomes that matter to patients, this trial makes dalteparin look harmful.

BIOMACS-II: Frostfeldt G, Ahlberg G, Gustafsson G, et al. Low molecular weight heparin (dalteparin) as adjuvant treatment of thrombolysis in acute myocardial infarction–a pilot study: biochemical markers in acute coronary syndromes (BIOMACS II). Journal of the American College of Cardiology. 1999; 33(3):627-33. [pubmed] [free full text]

This is another RCT of dalteparin versus placebo after streptokinase in STEMI patients. All of these patients went for angiography after being given thrombolytics. In 101 patients, they gave just 2 doses of dalteparin before follow-up angiography, and their primary outcome was TIMI grade flow on angiography. The trial was statistically negative, although the dalteparin group did have more TIMI grade 3 flow (68% vs 51%, p=0.1). However, that is a disease oriented surrogate outcome. They measured a number of clinical outcomes, and there were no statistical differences. However, I wonder whether the trial was simply underpowered to see significant harms with dalteparin (5 patients bled on dalteparin as compared to only 1 with placebo and 8 patients had reinfarction on dalteparin as compared to only 2 with placebo). Either way, despite the angiographic changes, there are no patient oriented benefits.

Bottom line: This was a negative trial. Dalteparin was unhelpful, or potentially harmful, although this trial was significantly underpowered.

AKI-SK: Simoons M, Krzemiñska-Pakula M, Alonso A, et al. Improved reperfusion and clinical outcome with enoxaparin as an adjunct to streptokinase thrombolysis in acute myocardial infarction. The AMI-SK study. European heart journal. 2002; 23(16):1282-90. [pubmed]

This is an RCT (blinding is unclear to me) that compared enoxaparin (one 30mg IV dose, then 1 mg/kg subcutaneously BID for 3-8 days) to placebo in 491 STEMI patients treated with streptokinase. The primary outcome was TIMI grade 3 flow on angiogram, and was only assessable in 389 of the patients. The number of patients with TIMI grade 3 flow was higher in the enoxaparin group (70.3% vs 57.8%, p=0.01). Death was the same in both groups (6.7% vs 7.0%), but reinfarction was lower with enoxaparin (2.4% vs 7.4%, p=0.01). (Non-fatal MI is an interesting outcome that sits on the fence between disease oriented and patient oriented. You really need long term follow-up data to tell the difference between a trivial troponin rise and a meaningful event. Also, reinfarction is more subjective than death, and it isn’t clear if this trial was blinded.) There was more major hemorrhage with enoxaparin, but the difference was not statistically significant (4.8% vs 2.5%). This is the first positive trial of heparin, but it is comparatively small and doesn’t look at a patient important outcome.

Bottom line: This trial has a high risk of bias. Enoxaparin showed benefit in a disease oriented primary outcome. It also showed a possible clinical benefit, although mortality is unchanged.

There were a few other trials that showed improved artery perfusion on follow up angiography when heparin was given, but the clinical (patient oriented) outcomes were not good, with more bleeding, and also non-statistically higher rates of reinfarction in the heparin groups. (de Bono 1992; Hsia 1990; Antman 2004)

CREATE: Yusuf S, Mehta SR, Xie C, et al. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA. 2005; 293(4):427-35. [pubmed]

This was the first and only trial to show a benefit in terms of patient oriented primary outcome with heparin. It is a 2×2 factorial design that also looked at GIK therapy (high dose insulin, glucose and potassium). For our purposes, it is a double blind trial of 15,570 patients from India and China with STEMI who were randomized to either reviparin (a LMWH) or placebo for 7 days. The trial has multiple “primary outcomes” and was not registered on ClinicalTrials.gov, so I cannot check the original study design. Overall, 73% of these STEMI patients received lytics (primarily streptokinase) and 6.1% underwent PCI. (Meaning more than 20% of these STEMI patients were not reperfused!) Aspirin was given to most patients, but only half received clopidogrel or an equivalent. The composite outcome of death, reinfarction, and stroke occurred in 11.0% of the placebo group and 9.6% of the reviparin group (HR 0.87; 95% CI 0.79-0.96; p =0.005). Death was statistically improved by 0.9% and reinfarction by 0.5%. Life threatening bleeding was also increased (0.9% vs 0.4%, p<0.01), as was intracranial hemorrhage (0.3% vs 0.1%). 

What should we make of this? By the numbers, this is clearly a positive trial, although the overall benefit (NNT of about 70) is not overwhelming. There are a couple major questions. Why was this trial positive when the others were negative? And, does this trial apply to our current clinical practice?

There are a few red flags with this trial, including the use of multiple co-primary outcomes and the fact that we cannot check the protocol using a resource like ClinicalTrials.gov. The various LMWHs may be quite different, and this is the only trial I have seen using reviparin. Furthermore, these patients are not quite like my STEMI patients, with only 50% getting dual antiplatelet therapy, the primary revascularization technique being fibrinolytics, and more than 20% of patients getting no revascularization at all. This is a really big deal, because the more treatments you add the harder it is to show benefit. (Once PCI lowers mortality by 3%, that is 3% fewer patients who could possibly benefit from heparin.) On the other hand, the more medications you add together, the more likely you are to see adverse events. They also excluded all patients “at high risk of bleeding”, so harm may have been under-estimated. Another possibility to consider whenever you have multiple negative trials and a single positive trial is that the trial was positive by chance alone.

Bottom line: If the mortality benefit seen here is real, it would be important, but there are numerous reasons to doubt this trial. I think we clearly need a replication, done in a setting with modern STEMI treatment, to be sure there is an overall net benefit.

Summary for heparin in the setting of fibrinolytics

The three earliest studies were clearly negative, with no benefit seen, and increased harms from bleeding. The AMI-SK study hints at benefit, but there is no mortality change, and the reduction in nonfatal reinfarction is partially balanced by an increase in major bleeding. The CREATE study shows a benefit in mortality, but it has a number of red flags for bias.

These trials leave us with a lot of questions. Should we consider the trials of unfractionated heparin and low molecular weight heparin separately? Is reviparin somehow better than the other LMWHs? Why are the results from these trials so heterogenous (some being definitively negative, while others seem positive)?

Scientifically, I think the best answer is that we need a replication of CREATE to really know if heparin results in net benefit for our patients. Clinically, I think it is fair to use LMWH after thrombolysis, but with the understanding that the benefit, if it exists, is quite small, and closely balanced by harms from bleeding. Knowing the numbers here, we should also feel comfortable with withholding heparin if clinical circumstances lead us to believe that the harms may outweigh the benefits.

One thing is certain: the evidence does not support strong, dogmatic statements that heparin is absolutely mandatory in these patients.

Is heparin required during PCI?

One of the reasons I put off exploring this evidence for years was that I was told that “heparin was absolutely necessary for all patients getting angiography or PCI”. What is the evidence for that claim?

The only real, placebo controlled trial of heparin in PCI provides pretty strong evidence that heparin is not necessary (and is probably harmful):

CIAO: Stabile E, Nammas W, Salemme L, et al. The CIAO (Coronary Interventions Antiplatelet-based Only) Study: a randomized study comparing standard anticoagulation regimen to absence of anticoagulation for elective percutaneous coronary intervention. Journal of the American College of Cardiology. 2008; 52(16):1293-8. [pubmed] [free full text]

This is a double-blind RCT that looked at 700 patients undergoing elective PCI for stable CAD. All patients were on dual antiplatelet therapy at the time of the procedure. They were randomized to unfractionated heparin (70-100 UI/kg) or placebo. The primary outcome was a composite of death, MI, and revascularization at 30 days, and placebo was noninferior to heparin. In fact, the numbers were worse for heparin, but just not enough to make placebo statistically superior (2.0% vs 3.7%; p=0.17 for superiority; p<0.001 for noninferiority). There were more periprocedural MIs in the heparin group (3.1% vs 1.7%; p<0.05). A number of different bleeding scores were used, but there was also more bleeding with heparin (about 1.5% vs 0%; only statistically significant for some scores). 

Bottom line: Not only is heparin not necessary for PCI in stable CAD, but it seems to result in worse outcomes. 

There are a couple retrospective studies as well. Although such studies are at significant risk of bias, I include them because they are the only studies that look at the question in the setting of ACS.

Laskey MA, Deutsch E, Barnathan E, Laskey WK. Influence of heparin therapy on percutaneous transluminal coronary angioplasty outcome in unstable angina pectoris. The American journal of cardiology. 1990; 65(22):1425-9. [pubmed]

This retrospective chart review looked at 305 unstable angina patients who underwent PCI. Base on APTT readings, they determined 135 received heparin for 24 hours before PCI and 169 didn’t. The study doesn’t provide any patient oriented outcomes, but for what they measured, heparin seemed to help. There were more successful PCI procedures (91% vs 81%) and less thrombus at the time of PCI. 

Caveats: This is clearly a disease oriented outcome rather than a patient oriented one. We now know that PCI doesn’t help patients with unstable angina, so it isn’t clear that having more successful procedures would matter.

Chen JY, He PC, Liu YH, et al. Association of Parenteral Anticoagulation Therapy With Outcomes in Chinese Patients Undergoing Percutaneous Coronary Intervention for Non-ST-Segment Elevation Acute Coronary Syndrome. JAMA internal medicine. 2018; PMID: 30592483

This is a retrospective review, looking at 6800 non-ST elevation ACS patients who underwent PCI. Patients who received heparin had the same rate of MI and death as those who did not receive heparin. The only difference between the groups was that heparin was associated with an increased rate of major bleeding. (Full write up here.)

Summary for heparin in PCI

As I said right at the outset, we really don’t have any good evidence that looks at heparin in the setting of PCI for MI (whether STEMI or NSTEMI). The retrospective study by Chen (2018) indicates harm from heparin in the real world, but is only an association. The strongest evidence we have from from CIAO, which clearly demonstrated harm from heparin in the setting of PCI for stable CAD. Although that may not be extrapolatable to PCI for STEMI, it clearly debunks the myth that “heparin is absolutely necessary for PCI”.

Other anticoagulants

Although I keep talking about heparin, we really want to know if any anticoagulant helps our STEMI patients. I focused on heparin to start, because all of the initial placebo controlled trials looked at heparin (either UFH or LMWH). Studies of other anticoagulants have used heparin as the control, rather than placebo.

Is low molecular weight heparin different?

Low molecular weight heparin has been studied against placebo. Those studies were discussed above, and aside from CREATE, they were negative. However, there are more studies that directly compare LMWH with UFH, and it seems pretty clear that LMWH is better.

One meta-analysis of 23 trials and 31,000 patients concluded that LMWH resulted in a 1.66% reduction in mortality, and a 1.2% reduction in major bleeding when compared to UFH. (Silvain 2012) However, without a comparison to placebo, it is hard to know what this means. LMWH was studied against placebo in conjunction with fibrinolytics without clear benefit. UFH was been studied again placebo in PCI and looks harmful. It is possible that LMWH provides some benefit, but it is also possible that LMWH is equivalent with placebo and the difference is explained by UFH causing harm. Either way, a 1% absolute reduction, or NNT close to 100, hardly supports statements that heparin is “absolutely necessary” in patients undergoing PCI for STEMI. Heparin is certainly not a parachute. 

Fondaparinux

Fondaparinux has not been compared to placebo for ACS. The OASIS-6 trial compared fondaparinux to UFH in 12,092 patients with STEMI. There was a 1.5% reduction in mortality (95% CI, 0.4%-2.6%). This difference only existed in the patients given lytics, while there was no difference in the PCI patients. (Yusuf 2006) Like LMWH, we are comparing to UFH, which might actually be worse than placebo, so it is hard to say whether fondaparinux results in net benefit over no treatment at all.

Bivalirudin

After lytics: The HERO-2 trial was a large RCT of bivalirudin versus unfractionated heparin in 17,073 MI patients who were treated with streptokinase. (White 2001) There was no difference in the primary outcome of mortality (10.8% vs 10.9%). There was a small decrease in reinfarction with bivalirudin (1.6% vs 2.3%; 0·70 [95% CI 0·56–0·87], p=0·001). There was no difference in major bleeding, but more moderate and minor bleeding with bivalirudin.

With PCI: A meta-analysis of 5 trials (10,350 patients) comparing bivalirudin to heparin in patients undergoing PCI for STEMI found no change in mortality, reinfarction, cardiovascular death. (Capopdanno 2016) There was a decrease in major bleeding with bivalirudin, but also an increase in stent thrombosis. However, worrying about which drug has fewer side effects seems silly if neither provides any benefit. Also, many of these trials were not a direct comparison to heparin alone, but to the combination of heparin and a glycoprotein 2a/3b inhibitor, which increases the bleeding risk. 

Conclusion

The practice of giving STEMI patients anticoagulation has never been based on strong evidence. There are no trials of heparin in STEMI patients undergoing PCI, and the trials of heparin in thrombolysed patients are mixed and have significant flaws. In NSTEMI and unstable angina patients, I think the evidence is clear: anticoagulation is harmful and should not be used. In STEMI, it isn’t clear to me whether anticoagulation results in a net benefit or harm. After reviewing the available evidence, I think it is clear that placebo controlled trials are necessary. Considering that a mortality benefit was been in CREATE, and in the meta-analysis comparing UFH to LMWH, I think we should probably be using LMWH (but not UFH) with STEMI patients who are given lytics until a replication study is completed. However, the data demonstrates that any benefit from low molecular weight heparin, if it exists, will be small, and tempered by the know bleeding harms. I think it is clearly a mistake to claim that heparin is “absolutely necessary”. If it helps, the absolute benefit will be in the range of 1%, not 100%. Therefore, heparin can clearly be withheld in patients with a very high risk of bleeding. However, there is enough uncertainty that, for now, I will probably continue to follow the available guidelines and prescribe low molecular weight heparin to most of my STEMI patients (while advocating for the much needed placebo controlled RCT).

Glossary

• ACS = acute Coronary Syndrome
• CAD = coronary artery disease
• LMWH = low molecular weight heparin
• MI = myocardial infarction
• NSTEMI = non-ST elevation myocardial infarction
• PCI = percutaneous coronary intervention
• STEMI = ST elevation myocardial infarction
• UFH = unfractionated heparin

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References

Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction–executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). Journal of the American College of Cardiology. 2004; 44(3):671-719. [pubmed] [free full text]

Capodanno D, Gargiulo G, Capranzano P, Mehran R, Tamburino C, Stone GW. Bivalirudin versus heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI: An updated meta-analysis of 10,350 patients from five randomized clinical trials. European heart journal. Acute cardiovascular care. 2016; 5(3):253-62. [pubmed]

Chen JY, He PC, Liu YH, et al. Association of Parenteral Anticoagulation Therapy With Outcomes in Chinese Patients Undergoing Percutaneous Coronary Intervention for Non-ST-Segment Elevation Acute Coronary Syndrome. JAMA internal medicine. 2018; PMID: 30592483

de Bono DP, Simoons ML, Tijssen J, et al. Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group trial. British heart journal. 1992; 67(2):122-8. [pubmed]

Eikelboom JW, Quinlan DJ, Mehta SR, Turpie AG, Menown IB, Yusuf S. Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials. Circulation. 2005; 112(25):3855-67. [pubmed]

Frostfeldt G, Ahlberg G, Gustafsson G, et al. Low molecular weight heparin (dalteparin) as adjuvant treatment of thrombolysis in acute myocardial infarction–a pilot study: biochemical markers in acute coronary syndromes (BIOMACS II). Journal of the American College of Cardiology. 1999; 33(3):627-33. [pubmed]

FUTURA/OASIS-8 trial group, Steg PG, Jolly SS, et al. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA. 2010; 304(12):1339-49. [pubmed]

GUSTO-I. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The New England journal of medicine. 1993; 329(10):673-82. [pubmed]

Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. Heparin-Aspirin Reperfusion Trial (HART) Investigators. The New England journal of medicine. 1990; 323(21):1433-7. [pubmed]

Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European heart journal. 2018; 39(2):119-177. [pubmed]

Kakkar VV, Iyengar SS, De Lorenzo F, Hargreaves JR, Kadziola ZA, . Low molecular weight heparin for treatment of acute myocardial infarction (FAMI): Fragmin (dalteparin sodium) in acute myocardial infarction. Indian heart journal. ; 52(5):533-9. [pubmed]

Kontny F, Dale J, Abildgaard U, Pedersen TR. Randomized trial of low molecular weight heparin (dalteparin) in prevention of left ventricular thrombus formation and arterial embolism after acute anterior myocardial infarction: the Fragmin in Acute Myocardial Infarction (FRAMI) Study. Journal of the American College of Cardiology. 1997; 30(4):962-9. [pubmed]

Laskey MA, Deutsch E, Barnathan E, Laskey WK. Influence of heparin therapy on percutaneous transluminal coronary angioplasty outcome in unstable angina pectoris. The American journal of cardiology. 1990; 65(22):1425-9. [pubmed]

Narins CR, Hillegass WB, Nelson CL, et al. Relation between activated clotting time during angioplasty and abrupt closure. Circulation. 1996; 93(4):667-71. [pubmed]

O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Circulation. 2013; 127(4). [free full text]

Silvain J, Beygui F, Barthélémy O, et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ (Clinical research ed.). 2012; 344:e553. [pubmed] [free full text]

Simoons M, Krzemiñska-Pakula M, Alonso A, et al. Improved reperfusion and clinical outcome with enoxaparin as an adjunct to streptokinase thrombolysis in acute myocardial infarction. The AMI-SK study. European heart journal. 2002; 23(16):1282-90. [pubmed]

Stabile E, Nammas W, Salemme L, et al. The CIAO (Coronary Interventions Antiplatelet-based Only) Study: a randomized study comparing standard anticoagulation regimen to absence of anticoagulation for elective percutaneous coronary intervention. Journal of the American College of Cardiology. 2008; 52(16):1293-8. [pubmed] [free full text]

White H, . Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet (London, England). 2001; 358(9296):1855-63. [pubmed]

Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006; 295(13):1519-30. [pubmed] [free full text]

Yusuf S, Mehta SR, Xie C, et al. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA. 2005; 293(4):427-35. [pubmed]

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A few other trials you might hear about:

• GUSTO-I: 20,000 patients treated with streptokinase comparing IV to subcutaneous heparin. No differences in death, reinfarction, or ischemic stroke. Increased bleeding in the intravenous group. (GUSTO 1993)
• FUTURA/OASIS-8: This trial is a little hard to interpret. It looks at patients with unstable angina or NSTEMI undergoing PCI. All patients were already on fondaparinux, and then they were randomized to either high dose, weight adjusted UFH or low fixed-dose UFH during the PCI procedure. So, it is really looking at dual anticoagulation. There was no statistical difference in the primary outcome (a composite of periprocedural bleeding and vascular access complications), although it did occur in 1.1% more patients in the high dose heparin group. There is a secondary outcome that they claim is better in the high dose heparin group. This is a combination of peri-procedural major bleeding, death, MI, and target vessel revascularization (3.9% vs 5.8%). I am skeptical of this for a number of reasons. First of all, they changed the definition of this composite from their original ClinicalTrials.gov posting. Second, the p value only equals 0.05, but isn’t less than 0.05, so many would say this wasn’t statistically significant. Also, their math seems to be faulty, as the number of patients who had the components of the composite don’t actually add up to the number they provide as the composite. Finally, neither important outcome (death or MI) was actually changed, so it isn’t clear that this composite means anything. Overall, it looks like you get basically the same outcomes whether you use a high or low dose heparin as your second anticoagulant. I don’t think it gives us any insight into whether heparin helps overall.