BMJ  2004;329:1248-1249 (27 November), doi:10.1136/bmj.329.7477.1248

Editorial

Angiotensin receptor blockers and myocardial infarction

These drugs may increase myocardial infarction—and patients may need to be told

The interpretation of large scale clinical trials is being increasingly scrutinised by leading journals,¹ with great emphasis being placed on the importance of sharing all potential side effects, no matter how trivial, with patients. The Lancet recently published the results of the valsartan antihypertensive long term use evaluation (VALUE) trial, a study of the effects of reducing blood pressure in patients at high risk.² The angiotensin receptor blocker valsartan produced a statistically significant 19% relative increase in the prespecified secondary end point of myocardial infarction (fatal and non-fatal) compared with amlodipine. A doctor who is a patient of one of the authors (SV) commented that if the incidence of myocardial infarction increased with valsartan it would be an essential component of informed consent to share this information when prescribing valsartan for high risk patients with high blood pressure. These peculiar results led us to examine carefully the evidence surrounding angiotensin receptor blocker and myocardial infarction.

Could the unexpected increase in the incidence of myocardial infarction in the VALUE trial represent a statistical aberration? Although the modest, yet significant differential in blood pressure in favour of amlodipine (1.8 mm Hg systolic and 1.5 mm Hg diastolic v amlodipine) may explain the 13% increase in the incidence of stroke in patients taking valsartan (P = 0.08), it is unlikely, according to some experts, to account for the 19% increase in the incidence of myocardial infarction.³

Unfortunately careful evaluation of the current evidence shows that angiotensin receptor blockers, unlike angiotensin converting enzyme inhibitors, are either neutral or increase the rates of myocardial infarction despite their beneficial effects on reducing blood pressure.

For example, the CHARM-alternative trial showed a significant 36% increase in myocardial infarction with candesartan (versus placebo) despite a reduction in blood pressure (4.4 mm Hg systolic and 3.9 mm Hg diastolic v placebo treatment).⁴ Likewise, in the CHARM-preserved study, candesartan reduced admissions for chronic heart failure by 13% but did not prevent death despite a mortality of 11.3% and a reduction in blood pressure of 7 mm Hg systolic and 3 mm Hg diastolic compared with placebo.⁵ In the study on cognition and prognosis in the elderly (SCOPE), candesartan was associated with a non-significant 10% increase in fatal plus non-fatal myocardial infarction despite lower blood pressure (3.2 mm Hg systolic and 1.6 mm Hg diastolic for candesartan v placebo).⁶ Furthermore, the angiotensin receptor blocker losartan in the LIFE study did not reduce rates of myocardial infarction despite a 1.7 mm Hg lower pulse pressure compared with atenolol.⁷ In the RENAAL trial, a study performed in diabetic patients with nephropathy, the angiotensin receptor blocker losartan offered nephroprotection, but no reduction in cardiovascular mortality, although about 30% of patients died of a cardiovascular event.⁸ In a similar population the angiotensin receptor blocker irbesartan showed nephroprotection⁹ but seemed to have no impact on the 24% incidence of cardiovascular events (a secondary composite end point). Although irbesartan lowered blood pressure (4 mm Hg systolic and 3 mm Hg diastolic v placebo), no reduction occurred in myocardial infarction, stroke, or cardiovascular death. Compared with amlodipine, irbesartan was associated with a 36% increase in non-fatal myocardial infarction (P = 0.06), a 48% non-significant increase in stroke, and a 29% non-significant increase in death despite similar blood pressure reduction (see advisory briefing of the Food and Drug Administration, NDA 20-757 (S-021), www.fda.gov).

These peculiar effects of angiotensin receptor blockers on myocardial infarction stand in contrast to those of angiotensin converting enzyme inhibitors, which consistently produce a 20% or greater reduction in myocardial infarction in patients with diabetes, hypertension, renal insufficiency, and atherosclerosis.

How could two pharmacological agents, considered by many to be interchangeable and equivalent, have such divergent effects on coronary vascular outcomes despite similar effects on blood pressure? Medicine contains several examples of similar pharmacological conundrums. For example, metformin and phenformin, agents of the same class that have similar effects on insulin sensitivity and glycaemic control, have different side effects, and phenformin is associated with a higher rate of lactic acidosis. Troglitazone, rosiglitazone, and pioglitazone are all thiazolidinedione insulin sensitisers, yet troglitazone was removed from the market because of increased rates of hepatocellular necrosis. Different statins have different side effects. Furthermore, pharmacological agents that held great promise for cardiovascular protection, such as hormone replacement therapy, have proved to be ineffective. If such profound differences exist between drugs in the same class, is it prudent to consider angiotensin receptor blockers and angiotensin converting enzyme inhibitors, drugs from two different classes, similar? Levy has recently provided some insight into how the angiotensin type II receptors may have harmful as well as beneficial effects.¹⁰

Has the time has come for clinicians, scientists, pharmacologists, and ethicists to review the unexpected effects of angiotensin receptor blockers on myocardial infarction and determine whether this should be part of the discussions between doctors and patients when starting treatment? In the interim, clinicians need to remember that treatment with valsartan at the initial dose used in the VALUE trial (80 mg) was associated with a significant increase in the incidence of myocardial infarction compared with amlodipine at the initial dose of 5 mg, although the incidence of cardiovascular death did not differ. Antihypertensive efficacy should not be confused with vascular protection, and until the results of large comparative trials such as ONTARGET/TRANSCEND¹¹ are available, it may be naive to consider that angiotensin receptor blockers are like angiotensin converting enzyme inhibitors but without the cough. Indeed, a recent comparison of these two classes of agents in diabetic nephropathy, has revealed a lack of benefit of angiotensin receptor blockers on mortality, despite renal protection.¹²

Division of Cardiac Surgery, Toronto General Hospital, Toronto, ON, Canada, M5G 2C4 (subodh.verma{at}sympatico.ca)

Division of Cardiology, North York General Hospital, North York, Canada, 4001 Leslie Street, North York, Ontario, M2K 1E1 (Dr.marty{at}bellnet.ca)

---

Competing interests: SV has received research grants and speaking honorariums from GlaxoSmithKline Canada, Aventis, Pfizer Canada, Actelion Canada, AstraZeneca Canada, and Merck/MerckFrosst Schering Canada. MS has received speaking honorarium from Aventis Canada, Novartis Canada, MerckFrosst Canada, Pfizer Canada, and AstraZeneca Canada.

References

1. Is GSK guilty of fraud? Lancet 2004;363: 1919.[CrossRef][ISI][Medline]
2. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363: 2022-31.[CrossRef][ISI][Medline]
3. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J. Heart outcomes prevention evaluation (HOPE) study. Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet 2001;358: 2130-1.[CrossRef][ISI][Medline]
4. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. CHARM Investigators and Committees. 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: 772-6.[CrossRef][ISI][Medline]
5. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-preserved trial. Lancet 2003;362: 777-81.[CrossRef][ISI][Medline]
6. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21: 875-86.[CrossRef][ISI][Medline]
7. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. LIFE Study Group. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359: 995-1003.[CrossRef][ISI][Medline]
8. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: 861-9.[Abstract/Free Full Text]
9. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345: 851-60.[Abstract/Free Full Text]
10. Levy BI. Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system. Circulation 2004;109: 8-13.[Free Full Text]
11. Teo K, Yusuf S, Anderson C, Mookadam F, Ramos B, Hilbrich L, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the ongoing telmisartan alone and in combination with ramipril global endpoint trial/telmisartan randomized assessment study in ACE intolerant subjects with cardiovascular disease (ONTARGET/TRANSCEND) trials. Am Heart J 2004;148: 52-61.[CrossRef][ISI][Medline]
12. Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 2004;329: 828.[Abstract/Free Full Text]

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