Angiotensin receptor blocker in patients with ST segment elevation myocardial infarction with preserved left ventricular systolic function: prospective cohort study
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g6650 (Published 14 November 2014) Cite this as: BMJ 2014;349:g6650
All rapid responses
ACE Inhibitors are Still the First of Choice.
Yang JH, et al’s paper investigated the association between treatment with an angiotensin receptor blockers (ARBs) and clinical outcomes in patients with ST segment
elevation myocardial infarction (STEMI) with preserved left ventricular systolic function and reported that ARBs showed beneficial effects comparable with angiotensin converting enzyme (ACE) inhibitors in these patients and suggested ARBs could be used as an alternative to ACE inhibitors in such patients.1
ACE inhibitors are beneficial and strongly recommended in patients with STEMI with heart failure, left ventricular systolic dysfunction, or with preserved left ventricular
systolic function because many clinical trials demonstrated the benefits of ACE inhibitors.2,3
In contrast, several clinical trials did not consistently demonstrate the benefits of ARBs. To be worst, myocardial infarction (MI) paradox had been suggested and paid caution in using ARBs.4,5 ARBs selectively block angiotensin II type 1 (AT1) receptor, which leads to a marked counterregulatory upregulation in angiotensin II. The resultant augmented angiotensin II release stimulates AT2 receptor and postreceptor signaling, which has been shown in humans to promote leukocyte dependent matrix metalloproteinase-1 release.6 This may explain, in part, the ARB-MI paradox. However, this hypothesis turns out to be false in patients now.
On the other hand, renin-angiotensin system (RAS) involves in many steps of atherosclerosis. Angiotensin II promotes superoxide anion generation and endothelial dysfunction. Angiotensin II activates nuclear transcription factor (NF-B) induced by oxidative stress, mediated by AT1 receptor.7 We reported pleiotropic effects of candesartan in addition to anti-hypertensive effect, that significantly improved flow-mediated vasodilation and reduced biomarkers of oxidant stress, inflammation, and hemostasis in patients with hypertension, independent of blood pressure reduction.8 Now patients with high risk such as myocardial infarction are required to take statins to prevent cardiovascular events. Of note, experimental and clinical studies demonstrated a cross-talk between hypercholesterolemia and RAS at multiple steps. Hypercholesterolemic rabbits display enhanced vascular expression of AT1 receptors that mediate increased activity of angiotensin II, thus increasing blood pressure.9 Statins reversed blood pressure elevating response to angiotensin II infusion by decreasing AT1 receptor density.10 Therefore, statins and ARBs may have potential to exert additive/synergistic beneficial effects in both endothelial function and insulin sensitivity when compared with monotherapy in patients with cardiovascular risk factors by both distinct and interrelated mechanisms (Fig. 1).11-13 We reported vascular and metabolic responses to therapies with statin and ARBs alone or in combination in hypertensive, hypercholesterolemic patients. Simvastatin combined with losartan improved endothelial function and insulin sensitivity in hypercholesterolemic, hypertensive patients.11 Recently, we observed that pravastatin combined with valsartan therapy improved flow-mediated vasodilation and reduced C-reactive protein, a biomarker of inflammation, and increased plasma adiponectin, lowered fasting insulin levels, and improved insulin sensitivity in an additive manner when compared with monotherapy alone in hypertensive population (Fig. 2).12
Although Yang JH, et al’s paper1 reported beneficial effects of ARBs comparable with ACE inhibitors in patients with STEMI with preserved left ventricular systolic function, still few studies have reported, compared with ACE inhibitors in such patients. Further, ACE inhibitors are cheaper than ARBs, albeit not rare dry coughing adverse effect. Therefore, the current guideline recommends the first use of ACE inhibitors in such patients and change to ARBs when intolerable to ACE inhibitors.2,3
Funding: None, Disclosures: None
REFERENCES
1. Yang JH, Hahn JY, Song YB, Choi SH, Choi JH, Lee SH, Jeong MH, Choi DJ, Park JS, Park HS, Gwon HC. Angiotensin receptor blocker in patients with ST segment elevation myocardial infarction with preserved left ventricular systolic function: prospective cohort study. BMJ 2014;349:g6650.
2. Task Force on the management of STseamiotESoC, Steg PG, James SK, Atar D, Badano
LP, Blomstrom-Lundqvist C, et al. ESC Guidelines for the management of acute myocardial
infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569-619.
3. O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, 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. Circulation 2013;127:e362-425.
4. Strauss MH, Hall AS. Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox. Circulation 2006;114:838-54.
5. Hall AS, Strauss MH. More about the "ARB MI paradox". Heart 2007;93:1011-4.
6. Kim MP, Zhou M, Wahl LM. Angiotensin II increases human monocyte matrix
metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications
for atherosclerotic plaque rupture. J Leukoc Biol 2005;78:195–201.
7. Koh KK, Oh PC, Quon MJ. Does reversal of oxidative stress and inflammation provide vascular protection? Cardiovasc Res 2009;81:649-59.
8. Koh KK, Ahn JY, Han SH, et al. Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll Cardiol 2003;42:905-10.
9. Nickenig G, Sachinidis A, Michaelsen F, et al. Upregulation of vascular angiotensin ii receptor gene expression by low-density lipoprotein in vascular smooth muscle cells. Circulation 1997;95:473-8.
10. Nickenig G, Baumer AT, Temur Y, et al. Statin-sensitive dysregulated at1 receptor function and density in hypercholesterolemic men. Circulation 1999;100:2131-4.
11. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation 2004;110:3687-92.
12. Koh KK, Lim S, Choi H, et al. Combination pravastatin and valsartan treatmenthas additive beneficial effects to simultaneously improve both metabolic and cardiovascular phenotypes beyond that of monotherapy with either drug in patients with primary hypercholesterolemia. Diabetes 2013;62:3547-552.
13. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol 2013;167:1696-702.
Competing interests: No competing interests
I read the article by Yang JH,et al with great interest, in which the authors compared 1-year prognostic impacts of angiotensin receptor blockers (ARBs) with angiotensin converting enzyme inhibitors (ACEIs) in patients with ST segment elevation myocardial infarction (STEMI) with preserved left ventricular systolic function who underwent primary percutaneous coronary intervention (PCI) [1]. I believe it would be appreciated if authors discuss the long-term survival benefit of ARBs before concluding that ARBs are as beneficial as ACEIs in STEMI patients with preserved left ventricular systolic function after PCI.
Although ARBs could be an alternative to ACEIs, a recent observational study using inverse probability of treatment weighting and propensity score matching methods revealed that patients treated with ACEIs had significantly lower long-term mortality compared with those treated with ARBs from 2 to 5 years after acute myocardial infarction [2]. This study also demonstrated that crude survival rates in patients with ARBs and without renin-angiotensin aldosterone system inhibitors were almost similar in the landmark analysis at 2-year time-point, which first made me suspicious about long term survival benefit of ARBs. If the drug continued to work and followed a proportional hazard assumption, survival difference between patients with and without the drug is supposed to increase continuously.
Thus, the above phenomenon can be explained by the possibility that ARBs lost survival benefit with long-term usage which might result in the change of hazard at 2-year time-point in that observational study. I completely understand that this study does not give us conclusive statement because this is just an observational study using information at discharge without any dosage or adherence information and is not a randomized controlled trial. However, a meta-analysis enrolling 26 randomized controlled trials and total of 108,212 patients at high cardiovascular risk without heart failure revealed that only ACEIs, but not ARBs, reduced the risk of all-cause death in the primary prevention setting [3].
I believe that these studies raise a new concern about the long-term survival benefit of ARBs in my opinion. To the best of my knowledge, however, this kind of concern has never been discussed elsewhere. Although direct comparison between patients with ARBs and placebo in high risk patients for cardiovascular disorder could not be performed due to ethical problem in a recent evidence based medicine era, further evaluation of this problem should be performed and mandatory if we continue to use ARBs in clinical practice. That’s why I believe it would be appreciated if the authors discuss the long-term survival benefit of ARBs before concluding that ARBs are as beneficial as ACEIs in STEMI patients with preserved left ventricular systolic function after PCI.
1. Yang JH,et al.Angiotensin receptor blocker in patients with ST segment elevation myocardial infarction with preserved left ventricular systolic function: prospective cohort study. BMJ. 2014;349:g6650.
2. Hara M, et al. Comparison of 5-year survival after acute myocardial infarction using angiotensin converting enzyme inhibitor versus angiotensin II receptor blocker. Am J Cardiol in press. (doi: 10.1016/j.amjcard.2014.03.055)
3. Savarese G, et al. A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure. J Am Coll Cardiol 2013;61:131-142.
Competing interests: No competing interests
Re: Angiotensin receptor blocker in patients with ST segment elevation myocardial infarction with preserved left ventricular systolic function: prospective cohort study
We thank Dr. Koh and Dr. Hara for comments on our study.
As Dr. Koh indicated, angiotensin converting enzyme (ACE) inhibitors are strongly recommended in patients with ST-segment elevation myocardial infarction (STEMI) with heart failure or left ventricular systolic dysfunction.1 2 ACE inhibitors are also a reasonable treatment for STEMI patients with preserved left ventricular systolic function.3 4 However, a substantial portion of patients are intolerant to ACE inhibitors due to adverse reactions such as the development of cough and angioedema.5 6 For example, the incidence of ACE inhibitor-induced cough is reported as high as about 40% in Koreans.7
Although Dr. Koh wrote that the current guideline recommends the first use of ACE inhibitors in patients with STEMI with preserved left ventricular systolic function and change to ARBs when intolerable to ACE inhibitors, current guidelines do not address the use of ARB in such patients.3 4 The above recommendation applies to STEMI patients with heart failure or left ventricular systolic dysfunction only. Unfortunately, data on the role of ARB in patients with acute STEMI and preserved left ventricular systolic function are lacking. Therefore, we sought to investigate the association of ARB therapy at discharge with clinical outcomes in STEMI patients with preserved left ventricular systolic function after primary percutaneous coronary intervention, using data from a nationwide, large-scale registry dedicated to myocardial infarction.
In the present study, ARBs showed beneficial effects comparable to ACE inhibitors in STEMI patients with preserved left ventricular systolic function.8 Our data suggest that ARBs can be used as an alternative to ACE inhibitors in STEMI patients with preserved left ventricular systolic function and those who are intolerant to ACE inhibitors may be one of the best candidates. Considering that the number of patients with preserved left ventricular systolic function is much greater than that of patients with depressed left ventricular systolic function after STEMI,9 the establishment of the role of ARB in patients with preserved left ventricular systolic function after STEMI is very important. We believe our study adds new knowledge on the role of ARBs after STEMI.
We read Dr. Hara’s article with great interest and would like to congratulate them on a nice study.10 As already mentioned in our article, a median follow-up of 12-months may be too short to conclusively determine the long-term efficacy of ARB therapy in the setting of STEMI. We take Dr. Hara’s comment seriously. However, there are substantial differences regarding characteristics of study population between Dr. Hara and his colleagues’ study and ours. While we included STEMI patients with preserved left ventricular systolic function after primary percutaneous coronary intervention, their study included patients with STEMI as well as those presenting with non-ST-segment elevation myocardial infarction. Data on left ventricular systolic function were not presented in their article. Therefore, it is difficult to compare the results of both studies directly. Moreover, both studies lacked data on doses administered, duration of prescription, and adherence. Large-scale, prospective randomized-controlled trials are needed to clarify the effects of long-term ARB therapy in low-risk patients with STEMI undergoing primary percutaneous coronary intervention.
References
1 Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Jr., Cuddy TE, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669-77.
2 Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333:1670-6.
3 Task Force on the management of STseamiotESoC, Steg PG, James SK, Atar D, Badano LP, Blomstrom-Lundqvist C, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569-619.
4 O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr., Chung MK, de Lemos JA, 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. Circulation 2013;127:e362-425.
5 McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. British Medical Journal 2006;332:1177-80.
6 Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008;372:1174-83.
7 Na SH, Lee, J.H., Lee, H.Y., Lee, S.Y., Kim, H.S., Chae, I.H., Sohn, D.W., Oh, B.H., Lee, M.M., Park, Y.B., Choi, Y.S., Lee, Y.W. Risk Factors of Angiotensin-Converting Enzyme Inhibitor-Induced Cough in Patients with Hypertension Korean Circulation J 2000;30:6.
8 Yang JH, Hahn JY, Song YB, Choi SH, Choi JH, Lee SH, et al. Angiotensin receptor blocker in patients with ST segment elevation myocardial infarction with preserved left ventricular systolic function: prospective cohort study. BMJ 2014;349:g6650.
9 Yang JH, Hahn JY, Song YB, Choi SH, Choi JH, Lee SH, et al. Association of beta-blocker therapy at discharge with clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. JACC Cardiovasc Interv 2014;7:592-601.
10 Hara M, Sakata Y, Nakatani D, Suna S, Usami M, Matsumoto S, et al. Comparison of 5-year survival after acute myocardial infarction using angiotensin-converting enzyme inhibitor versus angiotensin II receptor blocker. Am J Cardiol 2014;114:1-8.
Competing interests: No competing interests