11
This chapter will review the impact of advances in “secondary prevention,” defined here to encompass long-term medications prescribed to a patient who has already suffered a heart attack, which are intended to prevent another heart attack and to prolong life. These include aspirin, beta-adrenergic blockers, ACE inhibitors, as well as statins (which were discussed in Chapter 5). It will not address treatments like, nitrates, morphine, furosemide, and oxygen, which are given primarily to alleviate symptoms.
Aspirin
Acetylsalicylic acid (or aspirin), one of medicine’s most ancient remedies, has been part of the medical pharmacopeia since the late 1890s.1 It is derived from salicin, the active component of willow bark, which has been used for 4000 years to soothe pain and lower fevers. Although newer drugs like acetaminophen (Tylenol), ibuprofen (Advil, Motrin, Nuprin), and naproxen (Aleve) have displaced aspirin as the most popular over-the-counter analgesic and anti-pyretic drugs, aspirin has enjoyed a renaissance in the past few decades as an anti-platelet drug to prevent clotting after a heart attack or a non-hemorrhagic stroke. Unlike many other anti-clotting drugs (clopidogrel heparin, etc.), which are used mainly in conjunction with PCI and whose clinical impact is inseparable from that of the PCI procedure, the importance of aspirin in secondary prevention pre-dates and extends well beyond its use as an adjunct to PCI.
The first reported trial of aspirin to prevent cardiac mortality was conducted in the UK in 1971–74.2 In this trial, 1239 men with a recent MI were randomized to receive either a 300 mg daily dose of aspirin or a placebo. After two years of follow-up, mortality was 25% lower in the aspirin group than in the placebo group, with most of the divergence coming after eight months. Although this difference was not statistically significant because of the small number of deaths (108), and the results were clouded by high dropout rates, other investigators soon mounted bigger and better trials—and lots of them. By 1994, the Antiplatelet Trialists’ Collaboration was able to identify and review 145 randomized trials of antiplatelet therapies—mostly using aspirin.3 These included a large NHLBI-sponsored secondary prevention trial called Aspirin in Myocardial Infarction Study (AMIS) in 4524 post–MI patients.4 They also included two large NHLBI-sponsored primary prevention trials—the Physician’s Health Study (PHS) in 22,071 male physicians and the Women’s Health Study (WHS) in 39,876 female health professionals.5 Although the results of these three NHLBI trials were mixed, the Antiplatelet Trialists Collaboration found that antiplatelet therapy significantly reduced subsequent serious vascular events by 29% after an acute MI, by 25% after any MI, by 22% after a stroke, and by 32% in other high risk patients. However, it reduced cardiovascular risk by only 10% (borderline significant) in patients without prior cardiovascular disease. The impact on mortality was considerably smaller (17% in high risk groups and a non-significant 5% in patients without prior cardiovascular disease), since the benefit in atherothrombotic events was partially offset by an increased risk of fatal bleeds—particularly in the brain and gastrointestinal tract.
In 2009, a new updated meta-analysis—this time confined to aspirin—using individual patient data from six primary prevention trials (95,000 participants) and 16 secondary prevention trials (17,000 participants) reaffirmed and elaborated upon the 1994 analysis.6 In the six primary prevention trials, aspirin significantly reduced major coronary events by 18%, but also significantly increased hemorrhagic stroke by 32% and gastrointestinal bleeds by 54%. The net effect was a significant 12% reduction in serious vascular events, and a non-significant 3% decrease in vascular deaths. In the 16 secondary prevention trials, aspirin similarly significantly reduced major coronary events by 20% and significantly increased hemorrhagic strokes by 67% and gastrointestinal bleeds by 169%. However, because heart attacks comprised a much higher proportion of serious vascular events in these patients, aspirin produced a significant 19% net reduction in serious vascular events and a significant 13% net reduction in vascular deaths. This translates to 13 vascular deaths prevented per 1000 patients treated. With these results in hand, the U.S. Preventive Services Task Force recommended the use of aspirin in men age 45–79 and women age 55–79 in whom the potential risk reduction for a heart attack or atherothrombotic stroke is judged to outweigh the potential risk increase for a cerebral or gastrointestinal hemorrhage.7 In practice, this would include nearly all patients with a prior heart attack and would exclude most patients without known prior cardiovascular disease. The Task Force recommended that aspirin not be prescribed in younger patients (where it is likely to do more harm than good) and in patients aged 80 and above (who are more susceptible to severe bleeds and in whom clinical trial evidence benefit is lacking).
Beta-Adrenergic Blockers
Since a heart attack is generally accompanied by a rush of adrenaline and similar hormones (catecholamines), which stimulate the heart and cause heart rate and BP to rise, the advent of beta-adrenergic blockers in the 1970s for treating hypertension naturally suggested a potential application in blunting the potentially harmful effects of catecholamine release in acute MI. However, because beta-blockers decrease the pumping efficiency of a damaged heart (a negative inotropic effect in medical parlance), patients with decreased ventricular function or heart failure were exempted.
The first randomized placebo-controlled trials to test this hypothesis were the 1884-patient Norwegian Multicenter Timolol trial in 1981 and the 3387-patient NHLBI Beta-Blocker Heart Attack Trial (BHAT) in 1982. In the Norwegian trial, the beta-blocker timolol produced a significant 39% reduction in mortality in 33 months of follow-up.8 In BHAT, which was stopped early at 27 months, the beta-blocker propranolol significantly reduced mortality by 26%.9 In 1986, the 16,027-patient First International Study of Infarct Survival (ISIS-1) megatrial looked at the short-term impact of the beta-blocker atenolol on in-hospital mortality and found a non-significant trend toward reduced mortality.10 Based on these and other trials, beta-blockers became part of the standard therapy for uncomplicated acute MI with unimpaired ventricular function. Since beta-blockers lower BP, hypertensive patients often continued to take these drugs indefinitely after recovering from their acute MI.
Since the mid–1980s, many additional randomized trials have further explored the impact of beta-blockers on short- and long-term survival after an MI in various clinical settings. In 1999, Freemantle et al. published a meta-analysis of 82 such trials—51 of short-term survival (up to 6 weeks) and 31 of long-term survival (6–48 months)—in 54,234 MI patients randomized to a beta-blocker versus a placebo.11 This meta-analysis included some trials that were conducted after thrombolysis and angioplasty became standard treatments for acute MI, but most studies pre-dated the widespread use of these treatments. They reported that beta-blockers brought about a nonsignificant 4% decrease in short-term mortality but a significant 23% reduction in long-term mortality. They estimated that treating 42 acute MI patients with a beta-blocker for two years—it didn’t matter which one—would prevent one death.
In 2001, reports from a new beta-blocker trial called CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) revisited the question of using beta-blockers in acute MI patients with some left ventricular dysfunction—a group in whom beta-blockers were not ordinarily prescribed.12 They were able to do this because it had become standard practice to treat all such patients with an angiotensin converting enzyme (ACE) inhibitor (see below) to ameliorate their risk of heart failure. CAPRICORN randomized 1959 patients with acute MI and left ventricular ejection fraction below 40% to receive the beta-blocker carvedilol or a placebo. Nearly all randomized patients received aspirin in addition to an ACE inhibitor, and nearly half received primary angioplasty before carvedilol was initiated. Carvedilol treatment brought about a significant 23% reduction in long-term mortality over and above the effects of their ACE inhibitor, aspirin, and angioplasty. In 2005, the CAPRICORN trial reported that carvedilol also cut the incidence of atrial fibrillation (a potential precursor of strokes caused by clots forming in the left atrium and travelling to the brain) by more than half.13 Fast-forwarding to 2013–14, even after simple angioplasty had given way to PCI with drug-eluting stents, the latest ACC/AHA treatment guidelines for acute MI recommend oral beta-blockers for all MI patients without signs of heart failure, asthma, or heart block or risk factors for shock, although there is some question as to how long this treatment should continue.14 Carvedilol was also one of three beta-blockers cautiously recommended in non–STEMI patients with “stabilized” HF (i.e., treated with an ACE inhibitor or angiotensin receptor blocker). In 2017, metoprolol (#6), carvedilol (#29), atenolol (#36), propranolol (#41), nebivolol (#144), and timolol (#146) were the most frequently prescribed beta-blockers, accounting for a combined 142.4 million prescriptions.15
Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors
The kidneys (which secrete the enzyme renin) and adjacent adrenal glands (which secrete the hormone aldosterone) play a central role in regulation of blood volume and systemic vascular resistance.16 Although the detailed physiology is beyond the scope of this book, I will provide a brief summary. Renin cleaves a protein called angiotensinogen (which is produced in the liver) to angiotensin-I, which is in turn converted (by an enzyme called angiotensin converting enzyme [ACE]) to its active form, angiotensin-II. Among other things, angiotensin-II causes arteries to constrict (raising blood pressure) and the kidneys to retain more sodium (raising blood volume and thereby increasing the heart’s workload). Angiotensin-II also stimulates the adrenal cortex to release aldosterone, which further stimulates the kidneys to reabsorb sodium and lose potassium. The bottom line is that overactivity of the RAAS system is often a key player in the pathology of hypertension and congestive heart failure. So, naturally, this system has been a rich therapeutic target for these conditions.
The first RAAS-inhibiting drug, spironolactone, which dates back to 1960 but still ranks 69th with 11.6 million prescriptions in 2017, has enjoyed modest popularity as a second-line drug in treating hypertension and heart failure.17 In hypertension, it has often been used in combination with thiazide diuretics because it preserves potassium and thereby counterbalances their potassium-wasting effect.18 Since it is not used to treat acute MI and since we have already covered the benefits of BP control in Chapter 4, spironolactone will not be discussed further here. Instead, we will focus on the ACE inhibitors, which inhibit the activation of angiotensin, and the angiotensin receptor blockers (ARB) which block access of activated angiotensin to its target cells in the kidney, adrenals, and blood vessel walls.
The use of ACE inhibitors to treat hypertension and heart failure in the U.S. dates back to the FDA’s approval of captopril in 1981 and enalopril and lisinopril shortly thereafter.19 The Cooperative North Scandinavian Enalopril Survival Study (CONSENSUS, 1986), the NHLBI-sponsored Studies of Left Ventricular Dysfunction (SOLVD, 1991), and the second Veterans Administration Cooperative Vasodilator-Heart Failure Trial (V-HeFT II, 1991) soon established the utility of ACE inhibition (by enalopril) in reducing mortality in patients with moderate to severe chronic congestive heart failure.20
In 1992, the Survival and Ventricular Enlargement (SAVE) trial was the first to report the efficacy of an ACE inhibitor to treat acute MI.21 This trial randomized 2231 patients with acute MI and left ventricular dysfunction at 112 participating hospitals in the U.S. and Canada to receive either the ACE inhibitor captopril or a placebo 3–16 days after entering the hospital and followed them for an average of 42 months. About a third of patients received thrombolysis and another third received revascularization (mostly angioplasty) before they were randomized. Between 25% and 59% of patients in each treatment group also received aspirin, nitrates, calcium channel blockers, beta-blockers, diuretics, antithrombotic drugs, and digitalis (in decreasing order of frequency) in the first few days after their MI. In patients randomized to receive captopril, total and cardiovascular mortality and the worsening of heart failure were significantly reduced relative to placebo irrespective of other treatments they received. However, the incidence of myocardial re-infarction was similar in the captopril and placebo groups.
Two similar trials of ACE inhibition in acute MI reported similar results during the next five years. In the Trandolapril Cardiac Evaluation (TRACE) trial (1995), 1749 acute MI patients with significant left ventricular dysfunction (ejection fraction below 35%) were randomized to receive the ACE inhibitor trandolapril or a placebo within 3–7 days of hospitalization and followed for 24–50 months.22 As in SAVE, mortality and progression to severe heart failure—but not myocardial re-infarction—were significantly reduced. Then, in 1997, the 2006-patient Acute Infarction Ramipril Efficacy (AIRE) trial re-iterated the positive findings for heart failure progression and mortality and the negative findings for myocardial reinfarction SAVE and TRACE, but also reported significantly (30%) fewer sudden cardiac deaths in the ramipril group than in the placebo group.23 In retrospect, qualitatively similar reductions in sudden cardiac death were evident in SAVE and TRACE, but were ignored due to lack of statistical significance.
Having established the benefits of ACE inhibition in chronic heart failure and acute MI with impaired left ventricular function, the international Heart Outcomes Prevention Evaluation (HOPE) trial set out to explore the potential benefit of ACE inhibition in 9297 high-risk cardiovascular patients (i.e., those with a prior history of heart attack or diabetes plus at least one other cardiovascular risk factor) but normal ventricular function.24 The results were resoundingly positive. Ramipril treatment significantly reduced the combined incidence of MI, stroke, or death (the primary outcome) by 22%. Heart failure hospitalizations (of which there were many) and sudden cardiac deaths (of which there were few) were also significantly lower in the ramipril than in the placebo group. It is possible that some of the benefit was due to BP reduction, but fewer than 20% of HOPE participants had known hypertension.
Angiotensin receptor blockers (ARB) came into use in the late 1990s as better-tolerated alternatives to ACE inhibitors with a lower frequency of coughing and other side effects.25 They have to some extent ridden on the coattails of ACE inhibitor trials like SAVE, TRACE, AIRE, and HOPE, in claiming efficacy for secondary prevention of cardiovascular events. The evidence supporting the use of ARB in secondary prevention is weaker than that for ACE inhibitors, but trials comparing ARB to ACE inhibitors head-to-head have not shown significant differences. The ACCF/AHA guidelines give the nod to ACE inhibitors as the first line of therapy in patients who can tolerate their side effects because of their longer track record, but treat ARB as an essentially equivalent alternative for patients who cannot tolerate an ACE inhibitor.26 In 2017, 104.8 million prescriptions for lisinopril (plus another 16.7 million for a combination with hydrochlorothiazide) were written, making it the most prescribed drug in the U.S. Benazepril, enalapril, and ramipril are the only other ACE inhibitors in the top 200 prescription drugs of 2017, with about 21 million prescriptions combined.27 Among the ARBs, losartan potassium ranks ninth with 52 million prescriptions (plus another 11.8 million for a combination with hydrochlorothiazide), and valsartan ranks 85th with 9.2 million prescriptions (plus another 5.3 million for a combination with hydrochlorothiazide).
Digitalis
Digitalis, the most venerable drug in cardiology, is a cardio-active glycoside extracted from a species of foxglove plant, digitalis purpurea. Although the medicinal use of foxglove as an herbal remedy dates back to the ancient Greeks, the 18th-century Scottish physician William Withering is credited with the discovery and initiation of the modern use of digitalis extract to treat cardiac patients in 1775.28 In the early 1970s, when I was a medical student and intern, digoxin (the chief active component of digitalis) was a mainstay first-line treatment for heart attack patients, especially those with signs of heart failure (like pulmonary congestion and edema) and/or atrial fibrillation. Its efficacy was thought to derive from its potent positive inotropic effect, which enables a damaged heart to pump blood more efficiently, and its stabilizing effect on the specialized cardiac cells that generate and conduct the electric impulses that sustain a regular heartbeat.29 The main problem with digitalis has always been its extremely narrow therapeutic margin between the dosage required for efficacy and a toxic dose, which makes it a favorite poison among murder mystery authors. I learned about digitalis and foxglove from Agatha Christie long before attending medical school.
In February 1991, the NHLBI initiated the Digitalis Investigation Group (DIG) trial, a randomized placebo-controlled trial of digoxin in 6800 patients with chronic heart failure, as defined by left ventricular ejection fraction (the proportion of blood ejected by the left ventricle when it contracts) below 45%. In about 70% of the DIG patients, coronary ischemia was the cause of heart failure; 65% had had a prior heart attack, and 27% had angina pectoris. The results, published in 1997, indicated that mortality (the primary outcome) was totally unaffected by digoxin.30 However, digoxin did significantly reduce the rate of hospitalization for worsening heart failure. Today, digoxin is no longer recommended in the treatment of acute MI but is still viewed as a secondary treatment option for heart rate control in atrial fibrillation and to alleviate symptoms and reduce the need for hospitalization in congestive heart failure.31 The number of digoxin prescriptions in the U.S. has fallen by 78% from nearly 17 million in 2007 (42nd) to 3.74 million (168th) in 2017.32
Contribution of Secondary Prevention to the Decline in Heart Attack Mortality
We can dispense with digoxin right away because its usage has trended downward since 1970 and because it has no discernible effect on mortality. However, statins, aspirin, beta-blockers, and ACE inhibitors—and by extension angiotensin receptor blockers—all came on the scene for secondary prevention of heart attacks in the 1980s and have been staples of secondary cardiovascular prevention ever since. In their IMPACT model, Ford et al. attribute 8.5% of the observed decline in heart attack deaths between 1980 and 2000 to the use of statins, 8.0% to aspirin, 6.1% to beta-blockers, and 4.3% to ACE inhibitors (and other RAAS inhibitors) to treat patients who have already had a heart attack or other manifestation of atherosclerotic coronary heart disease (CHD).33 I derived these figures by combining the separate estimates for the impact of these treatments in acute MI, unstable angina, non-acute secondary prevention post–MI, secondary prevention post–PCI/CABG, chronic angina, heart failure (hospitalized and non-hospitalized), and hypertension. I have applied the method explained in the appendix and applied in Chapters 4–6 and to extrapolate these results to the current usage of these four treatments.34 Based on these increases in usage of these three secondary prevention treatments, I have estimated that 8.2% of the 81% decline in heart attack mortality rate could be attributed to statins, 8.1% to aspirin, 4.3% to beta-blockers, and 5.0% to RAAS inhibitors (see Table A.4 in the appendix). Note that, strictly speaking, some of this reduction in mortality (especially that attributed to RAAS inhibitors) might reflect prevention of heart failure deaths, which might be counted as other heart disease, rather than heart attack deaths. When we combine these four estimates to get a global estimate for secondary prevention (as we did for BP, LDL cholesterol, and smoking interventions in the primary prevention setting), we estimate that secondary prevention accounts for 23.3% of the of the 80.7% decline in heart attack mortality since 1968 (Table A.4). Although this figure represents less than half the contribution of primary prevention—reflecting the fact that these interventions apply only to the fraction of the population that has suffered and survived a heart attack or other CHD manifestation—these treatments still represent an important factor in the decline of heart attack mortality.
1. DR Ginsberg. Aspirin: turn-of-the-century miracle drug. Distillations, June 2, 2009. https://www.sciencehistory.org/distillations/aspirin-turn-of-the-century-miracle-drug.
2. PC Elwood, AL Cochrane, ML Burr, PM Sweetman, G Williams, E Welsby, SJ Hughes, R Renton. A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. BMJ 1974; 1:436–440.
3. Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy—I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81–106.
4. The Aspirin Myocardial Infarction Study Research Group. A randomized controlled trial of aspirin in persons recovered from a heart attack. JAMA 1980; 243:661–669.
5. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med 1989; 321:129–135. DOI: 10.1056/NEJM198907203210301.
6. Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009; 373:1849–1860.
Supplementary webappendix, https://researchonline.lshtm.ac.uk/id/eprint/19177/1/mmc1.pdf.
7. U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009; 150:396–404. https://doi.org/10.7326/0003-4819-150-6-200903170-00008.
8. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981; 304:801–807.
9. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 1982; 247:1707–1714.
10. First International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. Lancet 1986; 2:57–66.
11. N Freemantle, J Cleland, P Young, J Mason, J Harrison. Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999; 318:1730–1737.
12. The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomized trial. Lancet 2001; 357:1385–1390.
13. J McMurray, L Kober, M Robertson, H Dargie, W Colucci, J Lopez-Sendon, W Remme, DN Sharpe, I Ford. Antiarrhythmic effect of carvedilol after acute myocardial infarction. Result of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) Trial. JACC 2005; 45:525–530.
CM Pratt. Three decades of clinical trials with beta-blockers. The Contribution of the CAPRICORN trial and the effect of carvedilol on serious arrhythmias. JACC 2005; 45:531–532.
14. P O’Gara, FD Kushner, DD Ascheim, DE Casey, MK Chung, JA de Lemos, SM Ettinger, JC Fang, FM Fesmire, BA Franklin, CB Granger, HM Krumholz, JA Linderbaum, DA Morrow, LK Newby, JP Ornato, N Ou, MJ Radford, JE Tamis-Holland, CL Tommaso, CM Tracy, YJ Woo, DX Zhao. 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. JACC 2013; e78-e140.
EA Amsterdam, NK Wenger, RG Brindis, DE Casey, TG Ganiats, DR Holmes, AS Jaffe, H Jneid, RF Kelly, MC Kontos, GN Levine, PR Liebson, D Mukherjee, ED Peterson, MS Sabatine, RW Smalling, SJ Zieman. 2014 AHA/ACC Guidelines for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. JACC 2014; 64:e139-e228.
15. ClinCalc DrugStats Database. The top 200 drugs of 2020. https://clincalc.com/DrugStats/Top200Drugs.aspx.
16. J Speller. The Renin-Angiotensin-Aldosterone System. Teach Me Physiology, April 20, 2020. https://teachmephysiology.com/urinary-system/regulation/the-renin-angiotensin-aldosterone-system/.
17. ClinCalc DrugStats Database.
18. J Bryan. How spironolactone became the next best thing for severe heart failure. Pharmaceutical Journal, January 18, 2012. https://www.pharmaceutical-journal.com/news-and-analysis/how-spironolactone-became-the-next-best-thing-for-severe-heart-failure/11093181.article?firstPass=false.
19. DW Cushman, MA Ondetti. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension 1991; 4:589–592.
20. The Consensus Trial Study Group. Effects of enalopril on mortality in severe congestive heart failure. N Engl J Med 1987; 316:1429–1435. DOI: 10.1056/NEJM198706043162301.
The SOLVD Investigators. Effect of enalopril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293–302.
JN Cohn, G Johnson, S Ziesche, F Cobb, G Francis, F Tristani, R Smith, B Dunkman, H Loeb, M Wong, G Bhat, S Goldman, RD Fletcher, J Doherty, CV Hughes, P Carson, G Cintron, R Shabetai, C Haakenson. A comparison of enalopril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325:303–310.
21. MA Pfeffer, E Braunwald, LA Moye, L Basta, EJ Brown, TF Cuddy, BR Davis, EM Geltman, S Goldman, GC Flaker, M Klein, GA Lamas, M Packer, J Rouleau, JL Rouleau, J Rutherford, JH Wertheimer, CM Hawkins, on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992; 327:669–677.
22. L Kober, C Turp-Pedersen, JE Carlsen, H Bagger, P Eliasen, K Lyngborg, J Videbaek, DS Cole, L Auclert, NC Pauly, E Aliot, S Persson, AJ Camm, for the Trandolapril Cardiac Evaluation Study Group. A clinical trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333:1670–1676.
23. JGF Cleland, L Erhardt, G Murray, AS Hall, SG Bell, on behalf of the AIRE Study Investigators. Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A Report from the AIRE Study Investigators. Eur Heart J 1997; 18:41–51.
24. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000; 342:145–153.
25. S Bangalore, R Fakheri, B Toklu, G Ogedegbe, H Weintraub, FH Messerli. Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Patients Without Heart Failure? Insights From 254,301 Patients From Randomized Trials. Mayo Clin Proc 2016; 91:51–60.
26. P O’Gara, et al., and EA Amsterdam. ACCF/AHA Guidelines.
27. ClinCalc DrugStats Database.
28. The Digitalis Investigators Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336:525–533.
29. R Steckelberg, JS Newman. The fascinating foxglove. ACP Hospitalist, March 2010. https://acphospitalist.org/archives/2010/03/newman.htm.
30. FI Marcus. Editorial: Use of digitalis in acute myocardial infarction. Circulation 1980; 62:17–19.
31. SA Haji, A Mohaved. Update on digoxin therapy in congestive heart failure. Am Fam Physician 2000; 62:409–416.
32. Digoxin. Drug usage statistics, 2007–2017. https://clincalc.com/DrugStats/Drugs/Digoxin.
33. ES Ford, UA Ajani, JB Croft, JA Critchley, DR Labarth, TE Kottke, WH Giles, S Capewell. Explaining the Decrease in U.S. Deaths from Coronary Disease, 1980–2000. N Engl J Med 2007; 356:2388–2398. DOI: 10.1056/NEJMsa053935.
34. NS Shah, MD Huffman, H Ning, DM Lloyd-Jones. Trends in myocardial infarction secondary prevention: The National Health and Nutrition Examination Surveys (NHANES), 1999–2012. J Am Heart Assoc 2015; 4:1–12. doi:10.1161/JAHA.114.001709. https://www.ahajournals.org/doi/pdf/10.1161/JAHA.114.001709.