Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies

doi:10.1016/S0002-8703(99)70163-8

American Heart Journal

Volume 138, Issue 3, September 1999, Pages 577-585

https://doi.org/10.1016/S0002-8703(99)70163-8 Get rights and content

Abstract

Background Secondary coronary prevention studies have generally focused on specific medications, often to the exclusion of commonly used therapies. To date, long-term nitrate use has not been investigated in large-scale clinical trials. Methods and Results We examined the relation between long-acting nitrates given during the chronic phase of the disease and the outcome. We analyzed data prospectively acquired in a large, observational study involving 1042 patients enrolled for the Multicenter Study of Myocardial Ischemia (MSMI) in North America, Israel, and Japan as well as 1779 patients enrolled for the Multicenter Diltiazem Post Infarction Trial (MDPIT). The Cox analyses with all the variables retained revealed that nitrates were associated with a significantly increased mortality risk (MSMI: hazard ratio 3.78, P = .011; MDPIT: hazard ratio 1.61, P = .019) in patients who had recovered from an acute coronary event. The analyses with the propensity score method on the MSMI and the MSMI databases also showed that the risk for cardiac death with use of nitrates was increased in most of the 5 subclasses according to the score. Conclusion These analyses raise concern about the potential adverse effects of long-acting nitrate therapy in chronic coronary disease. (Am Heart J 1999;138:577-85.)

Section snippets

MSMI organization

Patients who were enrolled for the Multicenter Study of Myocardial Ischemia (MSMI) from 11 centers (15 hospitals) in the United States and Canada, 1 center in Israel, and 5 centers (7 hospitals) in Japan were analyzed for this study.6, 7 Each center had a principal investigator and one or more specially trained study coordinators responsible for the recruitment and follow-up of patients.

Patient recruitment

Enrollment in the study started on July 1, 1988, and ended on May 31, 1991, with follow-up through November

Clinical characteristics, medications, and habits of the patients

Clinical characteristics, medications, and habits of the study patients are shown in Table I.

. Clinical characteristics of patients (MSMI, n = 1042)

Characteristics	Population (%)
Mean age (yr)	58.4
Sex (male %)	77.2
Cardiac history
Previous MI	19.5
Angina	45.3
Hypertension	40.9
Insulin-dependent diabetes	5.2
Type of index event
Q-wave MI	45.4
Non-Q-wave MI	24.6
Unstable angina	29.1
Index hospitalization
Pulmonary congestion and/or rales	16.2
Thrombolytic therapy	30.7
PTCA	33.5
Interim history (between index hospitalization

Effect of long-term use of nitrates on long-term outcome

It has been demonstrated that intravenous administration of nitroglycerin in the setting of acute MI reduced infarct size¹³ and diminished the frequency of mechanical complications by improving postinfarction ventricular remodeling.¹⁴ Nitrates, including transdermal nitroglycerin, are frequently prescribed after acute MI, both prophylactically to prevent recurrent coronary events and for treatment of angina. Long-acting nitrates were administered in approximately a half of our patients.

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^☆: From the First Department of Internal Medicine, ^aShiga University of Medical Science and ^bKyoto University, and the ^cUniversity of Rochester Medical Center.

^☆☆: Supported in part by research grant HL-38702 from National Institute of Health, Bethesda, MD, and grants from Ciba-Geigy Corporation, Summit, NJ; Mallinckrodt Medical, Inc, St Louis, Mo; Marquette Electronics, Inc, Milwaukee, Wis; and Tanabe Seiyaku Co, Ltd, Osaka, Japan.

^★: Reprint requests: Yasuyuki Nakamura, MD, The First Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan. E-mail: [email protected]

^★★: 0002-8703/99/$8.00 + 0 4/1/98030

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Long-term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large-scale postinfarction studies☆,☆☆,★,★★

Abstract

Section snippets

MSMI organization

Patient recruitment

Clinical characteristics, medications, and habits of the patients

Effect of long-term use of nitrates on long-term outcome

Int J Cardiol

Am J Cardiol

J Am Coll Cardiol

Am Heart J

Am J Cardiol

Am J Cardiol

Am Heart J

Am J Cardiol

J Am Coll Cardiol

The beta-blocker heart attack trial

JAMA

Six-year follow-up of the Norwegian multicenter study on timolol after acute myocardial infarction

N Engl J Med

Secondary prevention reinfarction Israeli nifedipine trial (SPRINT). A randomized intervention trial of nifedipine in patients with acute myocardial infarction

Eur Heart J

The effect of diltiazem on mortality and reinfarction after myocardial infarction

N Engl J Med

Role of platelet inhibitor therapy in myocardial infarction

Cardiovasc Drugs Ther

Detection and significance of myocardial ischemia in stable patients after recovery from an acute coronary event

JAMA

Reducing bias in observational studies using subclassification on the propensity score

J Am Stat Assoc

Estimating causal effects from large data set using propensity score

Ann Intern Med

Regression models and life-tables

J R Stat Soc Bull

Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors

Stats Med

Assessing sensitivity to an unobserved binary covariate in an observational study with binary outcome

J R Statist Soc Bull

Reduction of CK and CK-MB indexes of infarct size by intravenous nitroglycerin

Circulation

Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications. Effect of timing, dosage, and infarct location

Circulation