Sir William Osler said it best, that learning medicine without books is like going to sea without a map, but learning medicine without patients is like not going to sea at all. Learning any aspect of medicine without the proper context of a real patient, is just learning facts then having to figure out how they fit together later.
Similarly, without proper framing of what your role is, a given subject can become overwhelming. Breaking it into specific sections, makes large subjects more manageable.
The question here is how do we manage a case of acute coronary syndrome. More specifically, what drugs help patients with STEMI, NSTEMI and UA?
STEMI – ST-segment elevation myocardial infarction
55 year old male presenting to the ED with chief complaint of STEMI. EMS transmitted 12-lead ECG from the ambulance and you’re preparing to receive the patient. The patient is otherwise awake, alert with vital signs that are not immediately concerning. What drugs does this patient need?
MONA-B is an acronym that was, and still is, taught to recall the main therapies of acute STEMI. Morphine, oxygen, nitroglycerin, aspirin, and beta blockers at one point were administered to all STEMI patients. While that is no longer the case, going through each one, and understanding its role, why it is useful and why we should or should not give it is important to know.
- The vitals:
- MOA: mu-opioid agonist
- Dose: 0.1 mg/kg IV, fixed 2-4mg IV
- Notes: improves coronary perfusion, but at what cost?
Morphine is a mu-opioid agonist and its use in ACS is both obvious and mysterious at the same time. What I mean by that is, ACS can be painful (chest pain, discomfort) so an analgesic agent makes sense. As a complimentary effect to this action, as it relieves pain, morphine can actually shift the oxygen supply-demand relationship to a more favorable range. By relieving pain, heart rate can be lowered, anxiety relieved which reduces stress (oxygen demand) on the heart. On top of that, improved cardiac output from a longer diastolic period (left ventricular filling time), the heart can perfuse it’s own tissue more effectively.
A key caveat here to understand is collateral perfusion. In an MI, there is an arterial obstruction that is preventing oxygenated blood from reaching tissue that needs it for ATP production (krebs cycle, oxidative phosphorylation). But the tissue around that ischemic core is being perfused by branches of other arterial vessels whos coverage overlaps the area perfused by the obstructed vessel. But this extra collateral flow can’t be sustained forever – but we can optimize it until the blockage is eliminated by percutaneous coronary intervention (PCI) or fibrinolysis.
Morphine’s action of reducing HR, optimizing coronary artery flow can help preserve this collateral blood flow action. But there are downsides to morphine.
In NSTEMI, morphine may increase mortality. The CRUSADE study was a non-randomized, retrospective, observational registry of NTEMI patients that included more than 57,000 patients. In this study, patients who received morphine with or without nitroglycerin, had higher mortality including risk adjusted mortality compared to patients who did not receive morphine. It’s not totally known why this happens. One theory is that with NSTEMI, if a patient receives morphine, they may not complain of as severe of pain and discomfort – making them seem less acutely ill, and subsequently delaying definitive care (PCI). While this is controversial, morphine use should be scrutinized in this population. Within the STEMI population, the FAST-MI suggested morphine does not have a net harmful effect.
It may also impair the GI absorption of other important drugs, namely the P2Y12 inhibitors.[4-7] Regardless of whether morphine is administered parenterally or orally, it can slow GI motility. With drug absorption, this can delay maximum absorption. When it comes to time critical medications, like the P2Y12 inhibitors, this leads to a clinically significant delay in absorption. Thinking of the context of this problem, the risk is early thrombosis of the stent or re-infarction of the tissue and recurrent MI. It’s controversial at this time, so there is poor guidance on what to do. While it’s also not know if this is a class effect with opioids, it’s safe to assume there is probably some delayed absorption.
Bottom line – After maximally tolerated nitrate therapy, is there a role for morphine in STEMI? It depends on weighing the balance of benefits (coronary perfusion) with the risks of early stent failure. With NSTEMI, the evidence is more clear that the risks may outweigh the benefits. So what’s the best way to relieve pain? Get the patient to the cath-lab and definitely resolve the MI.
- The vitals:
- Nasal cannula, mask or tube
- Might take your breath away
Supplemental oxygen is a logical solution to resolve the problem of demand-supply. However, it is not helpful in all patients. In fact, only patients who have an oxygen saturation of less than 90% on room air, should receive oxygen.[8, 9] Otherwise, it can lead to harm. It’s critical to recognize, nothing we do is without consequence. Even oxygen can lead to barotrauma, increased oxidative stress and inflammation, leading to larger myocardial infarction size if inappropriately administered.
Bottom line – oxygen should only be administered to patients with a room air oxygen saturation of less than 90%.
- The vitals:
- MOA: NO donor
- Dose: 0.4 mg SL (x1 then call 911 if no relief after 5 minutes), 5-50(?) mcg/min IV. Sprays, pastes, and patches too
Would you be surprised at this point if I told you not everyone should receive nitroglycerin for chest pain? Good. Not everyone should. The simple task of balancing risks to benefits is easy in a classroom or on paper, but in practice proves challenging. Nitroglycerin too, should be considered in this context and it can’t be understood without reviewing exactly what the benefits are. And it’s not mortality. In fact, nitroglycerin has only demonstrated that it improves subjective pain scores and comfort of patients. Yet, the risks can be as severe as cardiac arrest. So let’s examine nitroglycerin further.
Nitroglycerin acts to provide venodilation to reduce filling pressures aka preload, and (at high doses) produces arterial dilation that reduces afterload and improves coronary artery collateral blood flow. Nitroglycerin does this by acting as a nitric oxide supplement, increasing cGMP, decreasing intracellular calcium and producing smooth muscle relaxation.
This is useful in MI, and nitrates initiated within the first 24 hours of symptom onset reduces overall mortality in patients with ischemic chest paint.  That is, unless the patient is preload dependent. Meaning, because of ischemia (muscle damage) the only way the right ventricle can fill with blood is the end-diastolic force pushing blood into it. If that pressure is taken away, say by dilating the vena cava, the right ventricle cannot fill with blood, which in turn means the left ventricle receives less blood to perfuse not only just the coronary arteries but the rest of the body as well. Remember, each side of the heart operates in relation to the other. Learning each side of the heart and its function in school, brushes over this concept, yet it is critical to know for real-life patients.
Right-sided or inferior wall MI’s are the subtype of MI that nitroglycerin should be avoided in patients. These are the pre-load dependent patients. This can be thought of as being similar, in a way, to the drug-drug interaction of nitroglycerin with PDE-5 inhibitors. Phosphodiesterases metabolize NO, so if PDE is blocked, the NO hangs around longer and its effects last longer. Too much vasodilation/arterial dilation can be detrimental to the delicate balance required to maintain coronary artery perfusion, as well as perfusion to other vital organs.
Bottom line – Nitroglycerin at best improves patient comfort – and at worst kills them. Use wisely.
- The vitals: thromboxane A2 antagonist
- Dose: 81-324/5 mg PO
- Give it
Aspirin is the only drug in MONA that should be given due to proven benefit in all cause and MACE. The old ISIS-2 trial proved this, and there have been no additional data that have led us to believe otherwise. If you really want to get into it, the debates of dose can be interesting, but unless there is a history of anaphylaxis or ongoing major bleeding, patients with acute STEMI should receive 324/5 mg of aspirin, chewed.
Bottom line – Chew that aspirin! Or even inserting a suppository… get it in there!
- The vitals: beta2 selective antagonist
- Dose: 5mg IV, qbecareful
- Maybe increase cardiogenic shock, but in pre-PCI era?
In another effort to regain balance of oxygen supply-demand, the administration of beta-blockers to acute MI patients was once a standard practice. Slowing the heart rate would theoretically reduce oxygen demand and optimize perfusion and thus oxygen supply to cardiac tissue. The old practice of metoprolol 5 mg IV q15min x 3, followed by metoprolol tartrate 50mg PO q6h for 48 hours then transition to once daily metoprolol succinate targeting 200mg daily, repeated fell out of favor after the publication of the COMMIT-CCS 2 trial. In a nutshell, while the early administration of metoprolol improved CV-related outcomes, it increased mortality due to cardiogenic shock. The benefit was erased by this increased risk. As a result, we no longer routinely administer beta-blockers in acute MI. There are caveats to this. If a patient is tachycardic or hypertensive, one, or perhaps two doses of IV metoprolol may be appropriate, but certainly not the above defined scheduled dosing. Similarly, early administration, now defined as within 24 hours is still beneficial and should be done unless contraindications exist.[8, 9]
Bottom line – early aggressive beta blockers are not beneficial in STEMI, but should be given orally within 24 hours of presentation.
What’s nice to give early (in ED), but not necessary: heparin, P2Y12s and statins.
The patient received aspirin 324 mg, and was taken to the cath-lab for PCI. In as PCI was getting started, unfractionated heparin was started, eptifibatide and a dose of ticagrelor was administered orally.
The two main methods of managing acute STEMI are percutaneous coronary intervention or fibrinolysis.[7,8] There is a third method, coronary artery bypass grafting, but there is almost no pharmacotherapy with this so let’s just skip that for now. PCI is the process of placing a stent in the affected coronary artery to resolve the obstruction, and maintain vessel integrity. Stents are either bare-metal or drug-eluting (more on that in another section). The difference is relevant when considering antiplatelet therapy down the road, but actually there is very little difference in terms of drug management. Fibrinolysis is the parenteral administration of alteplase, tenecteplase or reteplase to break down the clot.[7,8,15] Both methods are still used, but have specific roles. In a nutshell, PCI is preferred, but if PCI cannot be performed within 120 minutes of first medical contact, fibrinolysis should be performed. Also, if the STEMI started less than 12 hours ago, fibrinolysis may be considered.[7,8,15]
In PCI, the drug therapy involved here is used to support the procedure, and prevent early stent failure from re-thrombosis. The two main strategies are heparin plus a GPIIb/IIIa inhibitor, or bivalirudin.[7,8] This is a hotly debated topic where there is no clear answer of which is better/safer. It boils down to which strategy the interventional cardiologist prefers.
With heparin, the dose is rather high. The traditional loading of 60 units/kg followed by 12 units/kg/hour is really for medical management, and not meant for inter-PCI heparin. In this setting, heparin is administered in very very high doses to a target activated clotting time (ACT). The ACT is used because the activated partial thromboplastin time (aPTT) is too unreliable at such high doses. Heparin is administered along with a GPIIb/IIIa inhibitor. The prefered agents are either eptifibatide or tirofiban, however abciximab was historically preferred. [7,8] These GPIIb/IIIa agents are antiplatelet in nature. This GPIIb/IIIa receptor is what fibrin anchors to, and links two platelets together. By blocking this receptor, no platelet aggregation, and no new clot formation. The heparin compliments this action by blocking the production of fibrin in the coagulation cascade.
Bivalirudin, a direct thrombin inhibitor, blocks the final activation of thrombin, thus preventing fibrin formation. Although not combined with an antiplatelet agent like a GPIIb/IIIa inhibitor, clinical evidence suggests a similar risk/benefit profile. The AHA doesn’t prefer one over the other.
Once the stent has been placed, however, this anticoagulation and antiplatelet action is stopped and the role of P2Y12 inhibition takes over. A note on timing: in order for these agents to become maximally effective, they need approximately 2 hours for absorption. So early administration is best, which can occur in the ED. However, all studies of P2Y12 agents had their loading dose administered in the cath-lab (periprocedural) or immediately afterwards in a cardiac recovery area. Therefore, practicing within evidence based medicine, it is reasonable to strategically administer P2Y12s after PCI/fibrinolysis – which can help streamline care and get patients to PCI faster.
Within the class of P2Y12 agents, there are three drugs to choose from: clopidogrel, prasugrel, and ticagrelor. As the names would suggest, clopidogrel and prasugrel share mechanistic and structural similarities, whereas ticagrelor is different.
The P2Y12 receptor exists on platelets and initiates a cascade of events leading to aggregation once activated by adenosine. Blocking adenosine, prevents platelet aggregation and preserves the reperfused coronary tissue and protects the stent. Clopidogrel and prasugrel irreversibly inhibit the receptor, so a new one has to be made. Ticagrelor reversibly inhibits this receptor, so it can regain its action. Does this make a difference? Not really – ticagrelor just has to be administered twice daily. There are, however, interesting adverse events related to ticagrelor ability to allow adenosine to work on other type of receptors (bradycardia, bronchospasm).
A loading dose of either agent is administered orally to rapidly achieve therapeutic concentrations, and followed by a maintenance dose. AHA states that patients should be taking a P2Y12 agent for at least one year, but could stay on them indefinitely at the discretion of the cardiologist. While there are not good long term studies on this, the risk balance here is bleeding risk. Should bleeding occur, there is no effective means of ‘reversing’ these agents.
So which agent is preferred? It depends. Ticagrelor appears to be more effective at reducing a composite outcome of major adverse cardiac events (MACE) compared to clopidogrel. Although ticagrelor has not be adequately compared to prasugrel, prasugrel has risk of excessive bleeding in patients with a who are going to undergo CABG, have a history of TIA or stroke, who are over the age of 75 or less than 60 kilograms. On the flip-side, prasugrel outperformed clopidogrel with respect to MACE in patients who are diabetic or overweight. Clopidogrel can still be used in patients who cannot afford the other agents.
There are numerous considerations with these agents that anyone caring for ACS patients must know. Drug-drug interactions with morphine and pharmacogenomic differences are the two most important.
Morphine can delay gut absorption of the P2Y12 inhibitors, leading to delayed maximum absorption. In NSTEMI, the consequence is early stent failure. In STEMI patients, there doesn’t seem to be a similar risk (see above MONA). The AHA isn’t sure what to do about this one, other than to think about it before giving morphine.
Since clopidogrel is a prodrug (they all are) that requires CYP2C19 metabolism for activation (only clopidogrel), it is subject to variations as a result in polymorphisms of the gene that leads to this isoenzyme production or function. In a nutshell, poor metabolizers won’t activate enough active drug, leading to stent failure. Over metabolizers will protect the stent, but have excessive bleeding. At this time, although we can test for these alleles, we don’t have an efficient way to do it in a timely fashion. If there is a concern, simply selecting either ticagrelor or prasugrel is sufficient.
So much more to talk about: Clopidogrel 600 vs 300, Ticagrelor 90 vs 60, Prasugrel 10 vs 5
Say the patient in in a rural critical access hospital, or the cath-lab is full or there was a natural disaster preventing the cardiologists from getting to the cath lab, what can be done for this patient?
Before fibrinolysis was a therapy for acute ischemic stroke, it was used as a reperfusion strategy in ACS. Although now it has fallen out of favor, in place of PCI. However, should patients meet criteria, and have no exclusion criteria (there are many), they may receive either alteplase, TNKase or reteplase followed by heparin or a low molecular weight heparin such as enoxaparin or fondaparinux. In patients receiving this strategy, UFH should be continued for at least 48 hours, or enoxaparin/fondaparinux should be continued for up to 8 days.[7,8]
The only P2Y12 agent that has been studied with fibrinolytic strategy is clopidogrel. In this setting, the loading dose must be 300 mg (not 600 mg).
The patient is out of PCI, where a DES was placed. Their heparin has been reversed and they’ve been loaded with ticagrelor. What additional drugs must they start within 24 hours?
At this point, we’re into secondary prevention. Meaning, the MI’s already happened- let’s help reduce the risk of another one happening. Statins, beta-blockers, ACE-inhibitors, aldosterone antagonists play the central role of drug therapy for secondary prevention.
High intensity statins should be started within 24 hours of the patient hitting the hospital door.[17, 18] Statins not only have a role in reducing LDL, but they have pleiotropic effects. Statins stabilize the plaque, reduce inflammatory processes and reduce the incidence of periprocedural MI.
Only two statins qualify for high intensity and at specific doses: atorvastatin 80 mg and rosuvastatin 40 mg. There is no proven benefit of one over the other.
Beta-blockers, as mentioned before, should be started within 24 hours. Their role in this phase of care is to prevent cardiac remodeling. Remodeling is the physiologic process that occurs in the heart after an MI to attempt to strengthen the myocardium and preserve cardiac output. The problem with remodeling is that it leads to cardiomyopathy (which can be a good thing – look at marathon runners) but then lead to dilated cardiomyopathy (a bad thing). Dilated cardiomyopathies cause heart failure, valve failure, and death. Since the process can be traced back to sympathetic activation, the logic here is to give a beta-blocker and blunt that aspect of pathophysiology. Beta-blockers have a proven mortality benefit here, as opposed to acute management. Furthermore, they play a role if a patient has underlying hypertension. BBs should be continued for at least 3 years, at which point, a shared decision making process should be undertaken to determine its ongoing use.[7,8,15,17]
Other beta blocker issues: diabetes/hypoglycemia, triglycerides
ACE-inhibitors, administered orally, should be started within 24 hours of presentation. ACEi’s role is similar to beta-blockers, to prevent cardiac remodeling. [7,8,19] They do this through RAAS inhibition. It’s important to remember that RAAS is activated not just by the actions of antidiuretic hormone, but also by the sympathetic nervous system as well. So beta-blockers and ACE-inhibitors have complimentary actions. If patient’s can’t tolerate ACEi cough, they can take ARBs. While the a patient can choose from any ACEi, the only ARBs recommended for use in this setting are candesartan, losartan and valsartan.[20, 21] If angioedema occurs from ACEi,(~3% incidence) it’s very risky to consider ARBs (0.7% risk). Direct renin inhibitors are not an alternative.
Aldosterone antagonists should be considered if the LVEF is < 40% after the MI in patients already taking an ACEi/ARB and a beta-blocker.[7,8, 22-24] This indication extends to patients who have heart failure symptoms or diabetes. Eplerenone has less anti-androgenic effects thant spironolactone.
Things not to do – lidocaine to suppress PVCs – Bad, but if for Vfib – good
- Rogers KC, Denus S, Finks SW, Spinler SA. Acute Coronary Syndromes. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861§ionid=146056870. Accessed December 13, 2018.
- Meine TJ et al. Association of Intravenous Morphine Use and Outcomes in Acute Coronary Syndromes: Results from the CRUSADE Quality Improvement Initiative. Am Heart J 2005. PMID: 15976786
- Puymirat E et al. Correlates of Pre-Hospital Morphine Use in ST-Elevation Myocardial Infartion Patients and its Association with In-Hospital Outcomes and Long-Term Mortality: The FAST-MI (French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction) Programme. Eur Heart J 2016. PMID: 26578201
- Hobl EL et al. Morphine Decreases Clopidogrel concentrations and Effects: A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Cardiol 2014. PMID: 24315907
- Hobl EL et al. Morphine Decreases Ticagrelor Concentrations but not its Antiplatelet Effects: A Randomized Trial in Healthy Volunteers. Eur J Clin Invest 2016. PMID: 26449338
- Hobl EL et al. Morphine Interaction with Prasugrel: A Double-Blind Cross-Over Trial in Healthy Volunteers. Clin Res Cardiol. 2016. PMCID: PMC4805697
- Parodi G et al. Morphine is Associated with a Delayed Activity of Oral Antiplatelet Agents in Patients with ST-Elevation Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Circ Cardiovasc Interv. 2014. PMID: 25552565
- O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78–140. [PubMed: 23256914]
- Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139–228. [PubMed: 25260718]
- Cabello JB et al. Oxygen Therapy for acute Myocardial Infarction. Cochrane Database Syst Rev 2016. PMID: 28595112
- Perez MI et al. Effect of Early Treatment with Anti-Hypertensive Drugs on Short and Long-Term Mortality in Patients with an Acute Cardiovascular Event (Review). Cochrane Database Syst Rev 2009. PMID: 19821384
- Randomised Trial of Intravenous Streptokinase, Oral Aspirin, Both, or neither Among 17,187 Cases of Suspected Acute myocardial Infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988. PMID: 2899772
- Chen ZM, et al. “Early intravenous then oral metoprolol in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial”. The Lancet. 2005. 366(9497):1622-1632
- Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44–122. [PubMed: 22070834]
- Huynh T, Perron S, O’Loughlin J, et al. Comparison of primary percutaneous coronary intervention and fibrinolytic therapy in ST-segment-elevation myocardial infarction: Bayesian hierarchical meta-analyses of randomized controlled trials and observational studies. Circulation 2009;119:3101–109. [PubMed: 19506117]
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- Smith SC Jr., Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: A guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol 2011;58:2432–2446. [PubMed: 22055990]
- Hulten E, Jackson JL, Douglas K, George S, Villines TC. The effect of early, intensive statin therapy on acute coronary syndrome: A meta-analysis of randomized controlled trials. Arch Int Med 2006;166:1814–1821
- Danchin N, Cucherat M, Thuillez C, Durand E, Kadri Z, Steg PG. Angiotensin-converting enzyme inhibitors in patients with coronary artery disease and absence of heart failure or left ventricular systolic dysfunction: An overview of long-term randomized controlled trials. Arch Int Med 2006;166:787–796.
- Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893–1906. [PubMed: 14610160]
- Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003;362:772–776. [PubMed: 13678870]
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709–717. [PubMed: 10471456]
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- Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. [PubMed: 21073363]