Eccentric Dosing of Nitrates Does Not Increase Cardiac Events in Patients with Healed Myocardial Infarction Ken KANAMASA, Norikatsu NAITO, Hideki MORII, Kazue NAKANO, Yasushi TANAKA, Koji KITAYAMA, Ryo HAKU, Tatsuya KAI, Osamu YONEKAWA, Yusuke NAGATANI, and Kinji ISHIKAWA＊, on Behalf of the Secondary Prevention Group
This study was performed to investigate the risk of cardiac events by eccentric or continuous dosing of nitrates in patients with healed myocardial infarction. A total of 573 patients with healed myocardial infarction were assigned to one of two groups: a nitrate-treatment (n＝239) and a nontreatment (n＝334) group. The nitrate-treatment group was further subdivided into a group receiving eccentric dosing of nitrates (n＝153) and a group receiving continuous dosing of nitrates (n＝86). The mean observation period was 11.2±8.2 months. The cardiac events investigated were nonfatal and fatal recurrent myocardial infarction, death from congestive heart failure, sudden death, worsening angina and rebound angina. Baseline characteristics were also compared among the three groups to determine any effects on outcome. Among the patients receiving eccentric or continuous dosing of nitrates, the rates of cardiac events were 12.7/1,000 person·year and 67.4/1,000 person·year, respectively, whereas the rate was 19.7/1,000 person·year in the nontreated patients. The incidence of cardiac events was significantly greater in patients receiving continuous dosing of nitrates than in the nontreated patients ( p＜0.05). Continuous dosing of nitrates thus increases cardiac events, and while eccentric dosing of nitrates does not increase them, it is also not effective at preventing them in patients with healed myocardial infarction. (Hypertens Res 2004; 27: 563–572) Key Words: nitrates, myocardial infarction, secondary prevention, cardiac events
Introduction The efficacy of short-term administration of nitrates for treating myocardial infarction during the acute phase has been well established (1–3). In 1999, the Committee on Management of Acute Myocardial Infarction reported that intravenous nitroglycerin was not useful for patients with systolic blood pressure (SBP) less than 90 mmHg or bradycardia less than 50 bpm (4). In 1993, the United States Food and Drug Administration Cardio-Renal Drugs Advisory Committee (5) concluded in their “Pink Sheet” that oral anti-anginal nitrates should be indicated only for single—i.e., not chronic-use, pending the availability of long-term data. The GISSI-3 (6)
and ISIS-4 (7) trials reported that nitrates gave no significant reduction in mortality and no long-term survival advantage. Ishikawa et al. (8) first reported in 1996 that long-term nitrates treatment increased cardiac events in patients with healed myocardial infarction. Moreover, Nakamura et al. (9) found that the use of long-acting nitrates in the treatment of chronic coronary artery disease may be associated with an increased risk of cardiac death. Continuous nitroglycerin patch application has been shown to have little clinical benefit because of the rapid development of nitrate tolerance (10–13). Studies on the use of intermittent therapy with a patch-free period of 10 to 12 h each day have documented clinical efficacy, but not for the entire period of patch application (14, 15). As our understanding of the mechanisms re-
From the Department of Vascular and Geriatric Medicine and ＊ Department of Cardiology, Kinki University School of Medicine, Osakasayama 589–8511, Japan. Address for Reprints: Ken Kanamasa, M.D., Department of Vascular and Geriatric Medicine, Kinki University School of Medicine, Ohno-Higashi 377–2, Osakasayama 589–8511, Japan. E-mail: [email protected]
Received December 24, 2003; Accepted in revised form May 7, 2004.
Hypertens Res Vol. 27, No. 8 (2004)
sponsible for nitrate tolerance has improved, particularly with respect to the documentation of neurohumoral activation (16) during nitrate therapy, there have been increasing concerns about the potential for rebound after patch removal during intermittent therapy. Rebound is a possible explanation for the reported increase in rest angina during the patchoff period in some patients receiving intermittent therapy with nitroglycerin (14, 17). The purpose of the present study was to clarify the risk of cardiac events by eccentric dosing of nitrates in patients with healed myocardial infarction.
(40 mg) or nitroglycerine patches (25 mg) were applied for 12 h, and new patches were applied each morning or evening. The nitrate prescriptions in both the continuous and eccentric treatments are shown in Table 1. The choice of oral (p.o.) or transdermal (patch) administration was made by the attending physician, as was the selection of eccentric or continuous dosing of nitrate treatment. Outpatient visits were scheduled approximately once a month after assignment during the study period. Informed consent was obtained before study entry. All studies were approved by the institutional review board.
Methods Follow-Up Examinations Recruitment of Patients
The participants in this clinical trial were 573 consecutive myocardial infarction patients in our department. Enrollment in the trial began in January 1997 and ended in December 1999. Patients of either gender and any age experiencing myocardial infarction during this period were eligible, including both inpatients and outpatients. Those who came to the outpatient clinic were registered on their first visit during the study period. Among inpatients, diagnosis of acute myocardial infarction was based on patient history, electrocardiographic changes compatible with acute myocardial infarction, and significant elevation of myocardial serum enzymes. Diagnosis of healed myocardial infarction was made from the characteristic electrocardiographic evidence of past myocardial infarction, with or without taking a history, and in the case of those who consulted our outpatient clinic, from medical documentation of acute myocardial infarction from the referring hospital. Assignment, Prescription and Follow-Up
Each patient was assigned an eight-digit identification number by the hospital administration on the first visit to our hospital before consultation by any doctors. Group assignment was performed using the 3rd-to-the-last digit of the identification number: if the digit was even (e.g., 99999299), the patient received nitrates treatment; if the digit was odd (e.g., 99999199), the patient was assigned to the untreated group. In both groups, sublingual or intravenous isosorbide dinitrate as well as nitroglycerin were used as required during the acute phase of myocardial infarction. Nitrates used for the treated group consisted of oral isosorbide dinitrate 20 mg or isosorbide mononitrate 20 mg twice a day (once each after breakfast and supper) or three times a day (once after each meal). The isosorbide dinitrate patches (40 mg) or nitroglycerine patches (25 mg) were applied for 24 h, and new patches were applied each morning or evening. Eccentric dosing of nitrate treatment consisted of oral isosorbide dinitrate 20 mg or isosorbide mononitrate 20 mg once a day (after breakfast) or twice a day (after breakfast and lunch). The isosorbide dinitrate patches
Inpatient heart rates and blood pressures were obtained as the daily means of the measurements made by the ward nurses at vital check-ups. Outpatient heart rates were measured from electrocardiograms recorded during follow-up, while the patients were at rest in the supine position in the electrocardiogram laboratory. Blood pressures for these patients were obtained as the means of casual blood pressures measured at our outpatient clinic. Serial blood tests, exercise electrocardiograms, and echocardiograms were administered to inpatients several times during their hospitalization, and approximately twice yearly to those treated in our outpatient clinic. Clinical severity during the acute phase was assessed by the Forrester (18) and Killip (19) classifications. Abnormalities in left ventricular wall motion were assessed by the wall motion index on 2-dimensional echocardiograms (20). Electrocardiogram QRS scores were determined to evaluate the extent of myocardial infarction (21). Angina pectoris during follow-up after myocardial infarction was diagnosed on the basis of the characteristic chest pain and prompt relief of the symptoms with sublingual nitroglycerin. Variant angina during follow-up was also diagnosed on the basis of chest pain as described by Prinzmetal et al. (22), prompt relief with sublingual nitroglycerin, with or without electrocardiographic evidence of transient ST segment elevation on the ambulatory electrocardiogram, and a positive response to provocation by ergonovine or acetylcholine. The exercise electrocardiogram was defined as positive if the patients showed a positive response in either Master’s two-step test or a treadmill exercise test. Exclusions and Discontinuation
Patients admitted to the hospital who survived 7 days after the onset of acute myocardial infarction were enrolled in the study; patients who died within 7 days after onset were excluded. Trial deviation was defined as discontinuation of study medication for more than 1 month for any reason other than a cardiac event or a doctor’s referral. When patients deviated from the protocol, they were dropped from the database. Investigation was continued in patients who received percutaneous transluminal coronary angioplasty (PTCA) or
Kanamasa et al: Eccentric Dosing of Nitrates
Nitrates A. Continuous treatment Slow-release ISDN 20 mg p.o. Slow-release ISMN 20 mg p.o. Transdermal ISDN 40 mg Transdermal ISDN 40 mg 24 h＋ Slow-release ISDN 20 mg p.o. Slow-release ISMN 20 mg p.o. Transdermal NTG 25 mg Transdermal NTG 25 mg 24 h＋ Slow-release ISDN 20 mg p.o. Slow-release ISMN 20 mg p.o.
tid (after every meal) bid (morning, evening) bid (morning, evening) 24 h
4 25 14 22
tid (after every meal) bid (morning, evening) 24 h
1 1 17
bid (morning, evening) bid (morning, evening)
B. Eccentric treatment Slow-release ISDN 20 mg p.o.
Slow-release ISMN 20 mg p.o.
Transdermal ISDN 40 mg Transdermal ISDN 40 mg morning–evening＋ Slow-release ISMN 20 mg p.o. Transdermal NTG 25 mg Transdermal NTG 25 mg morning–evening＋ Slow-release ISMN 20 mg p.o. Slow-release ISMN 20 mg p.o.
after breakfast after breakfast, lunch before sleep after breakfast after breakfast, lunch before sleep after breakfast, before sleep morning–evening night–morning
5 10 1 37 59 3 3 14 6
after breakfast, lunch morning–evening night–morning
2 7 4
after breakfast after breakfast, lunch
ISDN, isosorbide dinitrite; ISMN, isosorbide mononitrate; NTG, nitroglycerin; p.o., oral administration.
coronary artery bypass graft (CABG). Cardiac Events
The cardiac events of interest were nonfatal recurrent myocardial infarction, fatal recurrent myocardial infarction, death from congestive heart failure, and sudden death, worsening angina and rebound angina. Diagnosis of a recurrent myocardial infarction was made on the basis of the same criteria as the qualifying myocardial infarction for patient enrollment. Diagnosis of congestive heart failure was made from the signs and symptoms compatible with congestive heart failure, with or without echocardiographic, roentgenographic or hemodynamic evidence of heart failure. Diagnosis of death from congestive heart failure was established when
the cause of death was directly attributable to congestive heart failure. Sudden death, in accordance with Braunwald’s definition (23), was defined as death occurring unexpectedly with no premonitory symptoms or with symptoms lasting no longer than 1 h. Worsening angina was defined as an exacerbation of a patient’s usual symptoms requiring emergency hospital admission, and accompanied by objective evidence of ischemia from new or dynamic electrocardiographic abnormalities, a new or unequivocal regional wall motion abnormality, or scintigraphic perfusion defect indicating ischemia and extending over ≧2 myocardial segments (24). Rebound angina was defined as the increased frequency of angina attacks associated with decreased blood nitrate levels during nitrate-free intervals in patients receiving intermittent nitrate administration (25).
Hypertens Res Vol. 27, No. 8 (2004)
Characteristics of the Study Population No nitrates
Gender: male/female Age (years old) Blood pressure Systolic (mmHg) Diastolic (mmHg) Heart rate (beat/min) Atrial fibrillation (%) Inpatients/outpatients (n) Interval from onset to registration (month) Mean observation period (month) Assignment (%) Characteristics of MI at registry infarct site Anterior (%) Inferior (%) Non Q (%) Multiple (%) Forrester class (I/II/III/IV) (%) Killip class (I/II/III/IV) (%) Number of coronary vessels involved (I/II/III/LMT) (%) Peak CPK (U/l) Wall motion index by echocardiogram ECG QRS score Angina pectoris (%) Variant angina (%) Coronary risk factors Hyperlipidemia (%) Hypertension (%) Smoking (%) Diabetes mellitus (%) Obesity (%) Gout (%) Laboratory findings Uric acid (mg/dl) Fasting blood sugar (mg/dl) BUN (mg/dl) Creatinine (mg/dl) Plasma renin activity (ng/ml/h) Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL cholesterol (mg/dl) Positive exercise ECG test (%) Interventional therapy Coronary thrombolysis (%) PTCA (%) CABG (%) Combined medications Antiplatelet agents (%) Lipid lowering agents (%) β-blockers (%) Warfarin (%) Calcium antagonists (%) ACE inhibitors (%) Antiarrhythmic agents (%)
127±170 73±11 65±12 4.5 39/334 65.0±52.0 10.9±8.40 59.9
125±160 72±11 64±10 04.5 12/141 ＊ 75.6±55.5＊ 12.3±7.60 73.2
126±180 71±11 69±13 01.4 10/76 § 59.4±49.3§ 10.3±8.90 §§§ 51.2§§§
40.9 31.5 19.4 8.2 129/31/33/8 (64.2/15.4/16.4/4.0) 182/14/6/7 (87.1/6.7/2.9/3.3) 157/87/34/5 (55.5/30.7/12.0/1.8) 3,087±2,488 6.1±5.0 4.4±3.5 9.0 2.7
36.0 30.0 22.7 11.3 63/8/12/8 (69.2/8.8/13.2/8.8) 79/5/1/5 (87.8/5.6/1.1/5.6) 60/43/24/2 (46.5/33.3/18.6/1.6) 2,759±2,344 6.8±5.4 5.0±3.2 ＊＊ 19.0＊＊ 08.5
50.6 25.9 11.8 11.8 27/5/11/2 (60.0/11.1/24.4/4.4) 45/1/0/3 (91.8/2.0/0.0/6.1) 25/24/14/1 (39.1/37.5/21.9/1.6) 2,582±1,831 6.1±5.3 4.3±3.1 ＊ 16.3＊ 02.3
47.6 42.8 65.9 29.9 27.2 12.6
49.7 39.2 66.7 25.5 23.5 09.2
5.9±1.4 115±400 17±50 1.0±0.5 2.3±2.5 198±320 148±770 40.7±12.0 17.1
6.0±1.3 113±330 18±90 1.0±0.7 2.3±3.1 201±350 157±690 41.6±12.5 22.2
5.7±1.6 118±360 22±14 1.2±1.2 3.5±3.9 195±330 § 135±75§0 41.8±12.5 22.1
42.8 44.6 15.6
31.4 39.9 14.4
38.4 43.0 12.8
85.6 56.3 60.5 15.3 40.7 42.2 5.7
85.6 53.6 68.6 13.1 41.8 34.6 05.9
81.4 50.0 §§ 51.2§§ 15.1 41.9 33.7 08.1
44.2 55.8§ 61.6 32.6 29.1 10.5
Mean±SD. ＊ p