Introduction
Studies supporting the addition of a parental anticoagulant to aspirin in patients with NSTE-ACS were performed primarily on patients with a diagnosis of “unstable angina” in the era before dual anti-platelet therapy and early catheterization and revascularization. In general, those studies found a strong trend for reduction in composite adverse events with the addition of parenteral unfractionated heparin to aspirin therapy – AHA/ACC Guidelines 2014 0
1988 Threoux et al. Aspirin, heparin, or both to treat acute unstable angina.
0
1990 RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease.
1990 Cohen et al. 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).
1994 Holdright 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.
1994 Cohen 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.
1995 Gurfinkel et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia.
1996 FRISC group. Low-molecular-weight heparin during instability in coronary artery disease
0
1996 Oler et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina.
Because the anticoagulant effects of heparin are brief, any benefit of therapy is unlikely to last beyond the duration of treatment. Consistent with this theory, we found no reduction in the risk of MI or death between 2 and 12 weeks following randomization in patients with unstable angina who received heparin and aspirin compared to those who received aspirin alone. This result underscores that heparin is a short-acting, temporizing therapy, and not an intervention that alters underlying atherosclerotic disease. – Oler et al. 1996
Synthesis of the data
- Holdright 1994 used a 48-hour heparin infusion and evaluated event-free survival at 30 days. Since this study had plenty of time to evaluate the rebound of events following withdrawal of heparin, the results were negative. Note that the heparin group was doing better at day two, but this benefit promptly disappeared.
- Cohen 1994 used heparin followed by warfarin throughout the entire study period. These authors didn't observe a sharp rebound in event rates because they continued anticoagulation throughout the entire study.
- Gurfinkel 1995 found a benefit of low molecular-weight heparin, but not unfractionated heparin. This may reflect that unfractionated heparin wears off more quickly, leading to a faster rebound in infarction rate. The FRISC study showed that after stopping low molecular-weight heparin the rebound in reinfarction rate occurs over several days. The Gurfinkel study may not have followed patients long enough to observe this.
Implications for management of NSTEMI today
What do the European Society of Cardiology guidelines say?
Recurrence of events after interruption of unfractionated heparin explains why this benefit is not maintained over time, unless the patient is revascularized before the interruption of unfractionated heparin” – European Society of Cardiology guidelines 2011
What does the Cochrane Database say?
0
Limitations of the data
Take-home points
- AHA/ACC recommends anticoagulation with heparin as a Class I recommendation despite no proven benefit (the AHA/ACC bases this on a “strong trend for reduction in composite adverse events”).
- Heparin causes a temporary reduction in ischemic events, with a rebound in events following discontinuation. No placebo-controlled study has ever shown a sustained benefit from heparin.
- For NSTEMI patients treated with an invasive strategy, heparin makes sense as a temporary bridge to definitive revascularization with stenting or CABG surgery. However, this has never been proven in a prospective placebo-controlled RCT.
- For NSTEMI patients treated with a noninvasive strategy, heparin carries a significant risks of hemorrhage without offering any long-term benefit. In particular, the practice of using a 48-hour heparin infusion for patients treated with a noninvasive approach is not supported by evidence and should be abandoned (Holdright 1994).
(1) It is unclear exactly how long patients were on study therapy, given the multiple indications to stop study therapy.
- Pulmcrit wee: The cutoff razor - April 15, 2024
- PulmCrit Blogitorial – Use of ECGs for management of (sub)massive PE - March 24, 2024
- PulmCrit Wee: Propofol induced eyelid opening apraxia – the struggle is real - March 20, 2024
Good question, unfortunately there is no evidence-based answer. Studies evaluating heparin infusion were performed at a time before the STEMI/NSTEMI distinction was made. These studies only differentiated between Q-wave MI vs. non-Q wave MI. As such, the above studies on heparin actually included some STEMI patients. However, the studies contained predominantly NSTEMI patients, so it is difficult to extend these conclusions to STEMI patients. The utility of heparin has never been studied in STEMI patients specifically. The poor-prognosis shocked STEMI patient is a bit of a quandary. In general a heparin-only approach is likely to have a bad outcome (i.e.… Read more »
can this be applied to stemi? we have had stemi pts in our icu who cards did not want to take to the cath lab or even give thrombolytics because they were "too unstable" or had poor prognosis, wondering if continuing heparin on these people who would not be going to the cath lab does any good.
thanks-your blog is awesome by the way.
Thanks for your comments. I agree that it would be helpful to look at newer studies, but I've been unable to find any newer placebo-controlled studies. It gets murky when the studies are not placebo-controlled (i.e., if Drug A has better outcomes than Drug B, is that because Drug A is good or because Drug B is harmful?). For example, if you took 5,000 healthy people off the street and randomized them to unfractionated heparin vs. low molecular-weight heparin, the low molecular-weight heparin group would probably do better because low molecular-weight heparin is causing less harm. Perhaps we can agree… Read more »
Gosh. While this is a very considered and thoughtful piece, I can't help but worry that it completely misses the point. Of course heparin offers a short term benefit. There aren't many pharmacotherapies for a chronic disease (which is what atherosclerosis is, right?) which can offer survival benefit beyond their cessation. It is notable that you have criticized the studies as being from the pre-PCI era and therefore lacking in applicability, yet you have continued to use them as evidence against the use of heparin within the PCI era (there's a great diagram on one of your other blogs about… Read more »
Thanks so much. After having some disagreements with cardiologists over the years, it was refreshing to see exactly what the evidence said.
This is a reminder that specialty guidelines are not necessarily the final word with regards to their particular field. Indeed, specialty guidelines may have an inherent bias toward favoring interventions offered by that specialty (i.e., cardiac catheterization, thrombolysis for stroke, etc.).
Whoa! Intense post. Fantastic deep dive.
I think your take home points are spot-on with my interpretation of the literature, as well. Unless you're using the anticoagulation as a bridge to some other definitive intervention – PCI or CABG – there's no reason to expect any benefit, and simply exposing patients to bleeding risks. And, even then – it's unproven … but hard to make a case for clinical equipoise given the current state of practice. Would be a fantastic piece of dogmalysis if it were ever evaluated ….
Thanks for this synopsis! I admitted an NSTEMI to a hospitalist a few days ago with cardiology consulted & requesting Heparin infusion, which seemed standard to me. The hospitalist somewhat snarkily asked me why I bothered with Heparin, which initially seemed crazy to me. Did some searching around and found this and blew my mind a bit. Thanks for the reminder its always important to follow up on our assumptions!
Great post. I work as a GP in Australia and part time remote hospital Doc . Had a complex Aboriginal patient eGfr 3 , trop rise with chest pain settled , mild lateral ecg changes. Aspirin and Clopidogel given. Cardiology Reg wanted Heparin infusion. I didn’t think this was of any benefit with Medicare Management only and no intervention..they were quoting 2014 guidelines…..we argued…Guidelines are guidelines only….I was worriedaboutrebound..they should remember this. The remote ED Consultant was adamant about Heparin and then not sure when I argued the point. Guidelines are both useful and dangerous if one hangs off them..
Wow..could be one of the best posts yet and for Dr. Farkas that’s a huge mountain to climb. Alas, medico-legally could it hold up? Would you get takers? Say you give no heparin and they reinfarct 2wk later…?