- Email: [email protected]
Effect of nifedipine on out-of-hospital silent myocardial ischemia in asymptomatic men with coronary artery disease
908
BRIEF REPORTS
eluded in their report might resolve this discrepancy. Restenosis rates vary according to the definition used, and per patient rates are higher after multivessel compared with single-vessel PTCA. Restenosis has been correlated with procedural variables, such as the severity of residual stenosis and the absence of intimal dissection, and clinical variables, such as recent onset or unstable angina, diabetes and smoking.ll Hypercholesterolemia, absence of previous infarction and shorter duration of angina were the clinical characteristics that differed in our study patients compared with a control group with no restenosis. Clinical factors such as these may reflect an underlying pathophysiologic tendency favoring rcstenosis. Procedural variables may be easier to manipulate; larger balloons and higher inflation pressures were used for the third PTCA in this study. The slightly milder residual stenoses that resulted may have favorably influenced subsequent restenosis rates. In summary, a third PTCA is safe and effective treatment for recurrent restenosis. Although some patients may later require bypass surgery or another PTCA, most will eventually be asymptomatic. 1. Bertrand ME, Marco J, Cherrier F. Schmitt R. Gaspar PH, Puel J. Valeix B, Bory M. Crochet H, Geschwind H. Berland R, Machecourt J. Foucault 1P.
Effect of Nifedipine on Out-of-Hospital Silent Myocardial lschemia in Asymptqmatic Men with Coronary Artery Disease
Bassand IP, Bourdonnec CL, Quiret A, ]ault F. French percutaneous transluminaJ coronary angioplasty (PTCA) registry: four years experience (abstr). JACC 1966;7:21A\. 2. Holmes DR Jr, Vliestra RE, Smith HC. Vetrovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF, Detre KM, Van Raden MI. Mock MB. Restenosis after percutaneous iransluminal coronary angioplhsty (PTCA): a’ report from the PTCA registry of the.NHLBI. Am 1 Cardiol 1964;53:77C81C. 3. Dangoisse V, Guiteras Val P, David PR, Lesperance J. Crbpeau J. Dyrda I. Bourassa MG. Recurrence of stenosis after successful PTCA (abstr). Circulation 1982;66[suppl II]:II-331. 4. Williams DO, Gruentzig AR, Kent KM, Detre KM, Kelsey SF, To T. Efficacy of repeat PTCA for coronary restenosis. Am 1 CardioJ 1984;53:32C35C. 5. Meier B, King SB III. Gruentzig AR, Douglas JS, Hollman J, Ischinger T, Galan K, Tankersley R. Repeat coronary angioplasty. /ACC 1984;4:463466. 6. Mata LA, Bosch X, David PR, Rapold JH, Corcos T, Bourassa MG. Clinical and angiographic assessment6 months after double vesqel percutantious coronary angioplasty. JACC 1985;6:1239-1244. 7. Duprat G, David PR. Lespbrance 1, Guiteras Val P. Fines P. Robert P, Bourassa MG. An optimal size of balloon catheter is critical to angiographic success early after PTCA (abstr). Circulation 1984;7O(suppJII):&295. 8. Lambert M, Bonan R, CBt& G. Crepeau J, de Guise’P, Lesperance J, David PR, Waters DD. Early results, complications and restenosis rates after multilesion and multivessel perCutaneous transluminal coronary angioplasty. Am 1 Cardiol 1987;60:788-791. 9. Abi-Mansour P, Whitworth HB, Hoffmeister J. Douglas JS. King SB. Initial and late outcome aft&r a third coronary angioplasty-(PICA) foi recurrent native coronary restenosis(abstr). Circulation 1985;72(suppJIII):III-141. 10. Teirstein PS. Hoover C. Ligon B. Giorgi LV, Rutherford BD, McConahay DR, Johnson WL Jr, Harzler GO. Repeat restenosis: efficacy of the third and fourth coronary angioplasty (obstr]. JACC i987;9:63A. 11. Blackshear JL. O’Callaghan WG. Califf RM. Medical approaches to prevention of restenosisafter coronary angioplasty.IACC 1987:9:834.
mia of the calcium antagonist nifedipine standard therapeutic doses.
as used in
Our original patient group consisted of 15 male patients studied in our unit because of (1) no history of angina or anginal equivalents, (2) a positive but asymptomatic exercise test result and (3) coronary artery disease documented by coronary arteriography. None PETER F. COHN, MD of the patients was taking cardiac medications during WILLIAM E. LAWSON, MD the exercise tests or the subsequent ambulatory moniWith the technical assistance of toring period. Twelve of the 15 pati&ts demonstrated VIRGINIA GENNARO >I episode of ischemia on ambulatory electrocardioDOROTHY’ BRADY graphic (HoJter) monitoring during the initial 48 hours of monitoring and formed the final study group. Ambulatory electrocardiographic monitoring was performed (usually using leads Vl and V,] with a Del ost investigations using ambulatory electrocardiography to document episodes of myocardial ischemia Mar Avionics 445B &channel recorder, which has a during daily life have studied patients with angina.lm7 frequency response of 0.50 to 100 Hz and meet$ the American Heart Association’s specifications for heart This is also true of therapeutic trials with antiischemic agents.5-7Recently, however, 3 studie+lo have report- rate and ST changes. In our laboratory this system has ed the frequency and duration of ischemic episodes in been tested for reliability by comparing conventional coronary artery disease patients who do not have angi- l&lead electrocardiographic recdrdings during exercise tests to simultaneous HoJter recordings. Before a na, i.e., patients asymptomatic after myocardial infarcstudy, each patient underwent positional changes and tions or those who have never had symptoms. Information on drug therapy for these patients with silent myo- hyperventilation to assesslability of the ST segment; cardial ischemia is confined to 1 study with the 0 no baseline ST abnormalities were present, nor did blocker metoprololY The purpose of the present pilot any develop during these maneuvers. Recordings study was to test the effect on silent myocardial ische- we?e scanned on an Avionics’3100 scanner; electrocardiographic strips showing horizontaJ”or downslopFrom the Cardiology Division, Department of Medicine, State ing ST-segment depression of at least 1 mm, lasting ‘at University of New York Health Sciences Center (T-17-020) least 1 minute and sepqrated by 1 or .more minutes Stony Brook, New York. This study was supported in part by a from successive episodes were printed out and regrant from Pfizer Laboratories, Inc. Manuscript received Octoviewed in a blinded fashion. Patient diaries were also ber 28,1987; revised manuscript received and accepted Decemkept with patients instructed to record their daily acber 10.1987. tivities on an hourly basis, except, of course, when
M
April 15, 1988
TABLE I
Clinical,
Anglographic
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 61
909
and Holter Findings Holter Monitoring Nifedipine
Pretreatment Narrowed
CA
Pt
Right
LAD
LC
MI
lschemic Episodes (n)
1 2 3 4 5 6 7 8 9 10 11 12
+ + + 0 + + + 3 + 0 + +
+ 0 + + + + 0 + + + + +
+ 0 0 + + + 0 0 + 0 + +
0 0 +(A) +(A) 0 +(I) 0 0 0 0 +(A) 0
11 6 4 6 3 17 4 0 6 4 5 6
Duration of lschemic Episodes (min)
asleep. After giving informed consent, each patient was monitored for 48 hours consecutively and then given nifedipine therapy, either 10 or 20 mg orally 3 times a day. (Two patients received the larger dose because they had previously required it for blood pressure control). Two to 3 days later, patients underwent repeat 48-hour Holter monitoring. Coronary arteriography was performed in a standard manner. A significant lesion was one that occluded a major coronary artery or one of its large branches by at least 70%. Ah 22 patients were men aged 42 to 67 years. Three patients had prior Q-wave myocardial infarction (1 was unrecognized], and 1 patient had a prior non-Qwave infarction. The site of the infarctions and vessel stenoses on coronary arteriography is listed in Table I. Six of the 12 patients had 3-vessel disease. During the initial 796 hours of monitoring there were 80 episodes of silent ischemia. The number ranged from 3 to 17 (Table I). Total duration was 2,487 minutes with a range of 14 to 699 minutes. Heart rate at onset of ST depression ranged from 60 to 150 beats/ min with a mean of 88 f 8. As recorded in the diaries, activity during these episodes was usually not related to heavy exertion, A circadian variation was found: 32 of the 80 episodes (40%) occurred in the 6 A.M. to 22 noon time period. The total number of ischemic episodes decreased to 37 (p
lschemic Episodes (n)
Duration of lschemic Episodes (min)
4 4 1 1 4 5 1 0 6 7 0 4
143 144 2 10 21 59 2 0 55 177 0 2
699 153 I5 53 39 120 14 40 37 197 52 68
A = anterior: CA = coronarv artery:_. I = inferior: LAD = left anterior circumflex coronary artery; MI = myocardial infarction.
TABLE II
Treatment
descending
coronary
Effect of Treatment
artery: LC = left
on Hotter Findings
Pretreatment lschemic episodes (n) Duration of ischemic episodes (mitt) Heart rate at onset of episodes (beatsjmin) Episodes occurring between 6 A.M. and 12 noon (%) NS = difference
During Nifedipine Administration
p Value
80
37
1,487
625
<0.05
a7
88
NS
40
42
NS
not significant.
To date, 3 studies of asymptomatic patients with coronary artery disease and silent myocardial ischemia out-of-hospital have been published.s-*O Whether these patients should be treated and if so, with what agents, is unclear because pertinent prognostic data are limited. What studies are available show that prognosis in asymptomatic coronary populations with silent ischemia on exercise testing [with or without prior infarctions] appears to be related to the extent of vessel disease and the degree of left ventricular dysfunction. Certainly, if one were going to treat an asymptomatic population with antiischemic drugs, the subgroup of high-risk patients with 3-vessel disease and moderate left ventricular dysfunction would seem best suited for such trials (although coronary artery surgery is also an option in these patients). But what agents-or combinations of agents-should one choose? Choice of drugs can be empiric (based on antianginal experience) or can depend on the results of pilot studies with asymptomatic patients. In our pilot study, we used nifedipine, a calcium antagonist with well-documented coronary vasodilatory properties, because increased vasoconstrictor tone as a contributing mechanism to silent ischemia has been suggested by (1) the lower
910
BRIEF REPORTS
than expected heart rates observed during many silent ischemic episodes and (2) the relative infrequency of episodes related to strenuous exertion. In the present study we used standard doses of the drugs and no attempt was made to titrate to higher levels. One of the warnings in interpreting our study data is day-to-day variability of ischemic episodes. This is especially important since this was not a randomized placebo-controlled trial. Preliminary studies by Deanfield et aliz suggest that for a trial of this size, one would need to show at least a 50% decrease in ischemic episodes before one could attribute the reduction to therapeutic agents. In our study, this level was achieved. Further, despite the use of just 1 drug at low doses, 9 of the 12 patients had marked improvement in both ischemic frequency and duration. Our reduction in ischemic frequency and duration is comparable to that achieved by Imperi et alIf using low dose metoprolol(50 mg 2 times daily) although the mechanisms of action of these 2 drugs are obviously different. Even after treatment, we found the percentage of ischemic activity was still highest from 6 A.M. to 12 noon. This was also true in the study by Imperi et al. In summary, even in standard dosages, nifedipine was effective in reducing the frequency and duration of silent myocardial ischemia in our patient population. Based on this initial pilot study, it would appear reasonable to consider nifedipine for testing in large scale, randomized, placebo-controlled studies of asymptomatic patients with silent ischemia. (If higher doses are used, however, they probably should be combined with /3 blockers to reduce reflex tachycardia). These trials could be designed to explore not only
Relation of left Ventricular Free Wall Rupture in Acute Myocardial Infarction to Forced Immobilization CHRISTIAN TORP-PEDERSEN, MD FRANK STEENSGAARD HANSEN, MD ASGER PEDERSEN, MD 1 eft ventricular (LV] free wall rupture occurs in approximately 10% of fatal acute myocardial infarctions (AMI).l In 1 report2 73% of the deaths associated with myocardial infarcts among institutionalized psychotic patients were due to LV rupture. This raised the possibility of a relation between physical activity and LV rupture. In a later report3 no difference was observed between psychotic and nonpsychotic patients at the same hospital. At present it is unclear whether physical activity is a risk factor for LV rupture in myocardial infarcts. We studied 7,009 consecutive cases of AM1 for a possible relation between mobilization and LV rupture. From the Department of Cardiology, Glostrup County Hospital, DK2600 Glostrup, Denmark. Manuscript received May 14.1987; revised manuscript received and accepted November 24,1987.
the therapeutic benefits of antiischemic drugs, but also the prognostic implications of treating ischemic episodes-whether they are painful or not. 1. Schang S]. Pepine CJ. Transient asymptomatic S-T depression during daily activity. Am J Cardiol 1977;39:396-40.2. 2. Deanfield JE,Shea M, Ribiero P, deLandsheere CM, Wilson RA. Horlock P, Selwyn AP. Transient ST-segmentdepression as a marker of myocardial ischemia during doily life. Am r Cardiol 1984;54:1195-1200. 3. Gottlieb SO, Weisfeldt ML, Quyang P, Mellits ED, Gerstenblith G. Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med 1986;314:1214-1219. 4. Cecchi AC, Dovellini EV, Marchi F, Pucci P, Santoro GM, Fazzini PF. Silent myocardiol ischemia during ambulatory electrocardiographic monitoring in patients with effort angina. JACC 1983;1:934-939. 5. Johnson SM, Mauritson DR. Willerson IT, Hills LD. A controlled trial of verapamil for Prinzmetal’s variant angina. N Engl J Med 1981;304:862868. 6. Quyyumi AA, Wright C, Mockus L, Shackell M, Sutton GC. Fox KM. Effects of combined alpha and beta adrenoceptor blockade in patients with angina pectods: a double blind study comparing Jabetalol with placebo. Br Heart [ 1985:53:47-52. 7. Gottlieb SO, Weisfeldt ML, Ouyang P, Achuff SC, Baughman KL, Trail1 TA, Brinker JA. Shapiro EP, Chandra N, Mellits ED, Townsend SN, Gerstenblith G. Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized. double-blind, placebo-controlled trial. Circulation 1986;73:331-337. 6. Campbell S. Barry J,Rebecca GS, Rocco MB, Nable EG, Wayne RR, Selwyn AP. Active transient myocardial ischemia during daily life in asymptomatic patients with positive exercise tests and coronary artery disease. Am 1 Cardiol 1986;57:1010-1016, 9. Coy KM, Imperi GA, Lambert CR, Pepine CJ. Silent myocordial ischemia during daily activities in asymptomatic men with positive exercise test responses. Am J Cardiol 1987;59:45-49. 10. Cohn PF, Lawson WE. Characteristics of silent myocardial ischemia during out-of-hospital activities in asymptomatic ongiographically documented coronary artery disease. Am J Cardiol 1987;59:746-749. 11. Imperi GA, Lambert CR, Coy K, Lopez L. Pepine CJ. Effects of titrated beta blockade (metoprolol] on silent myocardial ischemia in ambulatory patients with coronary artery disease. Am J Cardiol 1987;60:519-524. 12. Deanfield JE, Selwyn AP, He&y MJ. Variability of “stable angina” revealed by ST Holter monitoring: implications for clinical investigation (abstr). Circulation 1986;74(suppJII):40.
GJostrup County Hospital serves a well-defined urban and suburban area in Copenhagen, Denmark, with a population between 250,000 and 350,000. The coronary care unit receives all cardiac emergencies in the region. AMI is rarely treated at home. We have analyzed all cases of AMI admitted during the period 1959 to 1983. From 1959 to 2977 the diagnosis of AM1 was based strictly on the World Health Organization criteria.4 After 2977 a transient increase in serum JeveJsof the heart-specific creatine kinase isoenzyme in patients with a supposed onset of AMI within the preceding 36 hours was considered a prerequisite for the diagnosis. In a study from this department5 positive and negative predictive values of the transient increases in creatine kinase isoenzyme were 0.98 and 1.00 compared with the World Health Organization criteria. AM1 was assumed to take place at the onset oj severe chest pain. This time was well defined in all cases of LV rupture but 6. In all patients with LV rupture who survived more than a few hours after admittance, increased levels of creatine kinase isoenzyme or aspartate aminotransferase were demonstrated. In no case did autopsy indicate that the infarct was older than estimated by the onset of chest pain. Postmortem examination was performed routinely in all patients who died from known or suspected AMI. Data were available in 91% of fatal cases. The
BRIEF REPORTS
eluded in their report might resolve this discrepancy. Restenosis rates vary according to the definition used, and per patient rates are higher after multivessel compared with single-vessel PTCA. Restenosis has been correlated with procedural variables, such as the severity of residual stenosis and the absence of intimal dissection, and clinical variables, such as recent onset or unstable angina, diabetes and smoking.ll Hypercholesterolemia, absence of previous infarction and shorter duration of angina were the clinical characteristics that differed in our study patients compared with a control group with no restenosis. Clinical factors such as these may reflect an underlying pathophysiologic tendency favoring rcstenosis. Procedural variables may be easier to manipulate; larger balloons and higher inflation pressures were used for the third PTCA in this study. The slightly milder residual stenoses that resulted may have favorably influenced subsequent restenosis rates. In summary, a third PTCA is safe and effective treatment for recurrent restenosis. Although some patients may later require bypass surgery or another PTCA, most will eventually be asymptomatic. 1. Bertrand ME, Marco J, Cherrier F. Schmitt R. Gaspar PH, Puel J. Valeix B, Bory M. Crochet H, Geschwind H. Berland R, Machecourt J. Foucault 1P.
Effect of Nifedipine on Out-of-Hospital Silent Myocardial lschemia in Asymptqmatic Men with Coronary Artery Disease
Bassand IP, Bourdonnec CL, Quiret A, ]ault F. French percutaneous transluminaJ coronary angioplasty (PTCA) registry: four years experience (abstr). JACC 1966;7:21A\. 2. Holmes DR Jr, Vliestra RE, Smith HC. Vetrovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF, Detre KM, Van Raden MI. Mock MB. Restenosis after percutaneous iransluminal coronary angioplhsty (PTCA): a’ report from the PTCA registry of the.NHLBI. Am 1 Cardiol 1964;53:77C81C. 3. Dangoisse V, Guiteras Val P, David PR, Lesperance J. Crbpeau J. Dyrda I. Bourassa MG. Recurrence of stenosis after successful PTCA (abstr). Circulation 1982;66[suppl II]:II-331. 4. Williams DO, Gruentzig AR, Kent KM, Detre KM, Kelsey SF, To T. Efficacy of repeat PTCA for coronary restenosis. Am 1 CardioJ 1984;53:32C35C. 5. Meier B, King SB III. Gruentzig AR, Douglas JS, Hollman J, Ischinger T, Galan K, Tankersley R. Repeat coronary angioplasty. /ACC 1984;4:463466. 6. Mata LA, Bosch X, David PR, Rapold JH, Corcos T, Bourassa MG. Clinical and angiographic assessment6 months after double vesqel percutantious coronary angioplasty. JACC 1985;6:1239-1244. 7. Duprat G, David PR. Lespbrance 1, Guiteras Val P. Fines P. Robert P, Bourassa MG. An optimal size of balloon catheter is critical to angiographic success early after PTCA (abstr). Circulation 1984;7O(suppJII):&295. 8. Lambert M, Bonan R, CBt& G. Crepeau J, de Guise’P, Lesperance J, David PR, Waters DD. Early results, complications and restenosis rates after multilesion and multivessel perCutaneous transluminal coronary angioplasty. Am 1 Cardiol 1987;60:788-791. 9. Abi-Mansour P, Whitworth HB, Hoffmeister J. Douglas JS. King SB. Initial and late outcome aft&r a third coronary angioplasty-(PICA) foi recurrent native coronary restenosis(abstr). Circulation 1985;72(suppJIII):III-141. 10. Teirstein PS. Hoover C. Ligon B. Giorgi LV, Rutherford BD, McConahay DR, Johnson WL Jr, Harzler GO. Repeat restenosis: efficacy of the third and fourth coronary angioplasty (obstr]. JACC i987;9:63A. 11. Blackshear JL. O’Callaghan WG. Califf RM. Medical approaches to prevention of restenosisafter coronary angioplasty.IACC 1987:9:834.
mia of the calcium antagonist nifedipine standard therapeutic doses.
as used in
Our original patient group consisted of 15 male patients studied in our unit because of (1) no history of angina or anginal equivalents, (2) a positive but asymptomatic exercise test result and (3) coronary artery disease documented by coronary arteriography. None PETER F. COHN, MD of the patients was taking cardiac medications during WILLIAM E. LAWSON, MD the exercise tests or the subsequent ambulatory moniWith the technical assistance of toring period. Twelve of the 15 pati&ts demonstrated VIRGINIA GENNARO >I episode of ischemia on ambulatory electrocardioDOROTHY’ BRADY graphic (HoJter) monitoring during the initial 48 hours of monitoring and formed the final study group. Ambulatory electrocardiographic monitoring was performed (usually using leads Vl and V,] with a Del ost investigations using ambulatory electrocardiography to document episodes of myocardial ischemia Mar Avionics 445B &channel recorder, which has a during daily life have studied patients with angina.lm7 frequency response of 0.50 to 100 Hz and meet$ the American Heart Association’s specifications for heart This is also true of therapeutic trials with antiischemic agents.5-7Recently, however, 3 studie+lo have report- rate and ST changes. In our laboratory this system has ed the frequency and duration of ischemic episodes in been tested for reliability by comparing conventional coronary artery disease patients who do not have angi- l&lead electrocardiographic recdrdings during exercise tests to simultaneous HoJter recordings. Before a na, i.e., patients asymptomatic after myocardial infarcstudy, each patient underwent positional changes and tions or those who have never had symptoms. Information on drug therapy for these patients with silent myo- hyperventilation to assesslability of the ST segment; cardial ischemia is confined to 1 study with the 0 no baseline ST abnormalities were present, nor did blocker metoprololY The purpose of the present pilot any develop during these maneuvers. Recordings study was to test the effect on silent myocardial ische- we?e scanned on an Avionics’3100 scanner; electrocardiographic strips showing horizontaJ”or downslopFrom the Cardiology Division, Department of Medicine, State ing ST-segment depression of at least 1 mm, lasting ‘at University of New York Health Sciences Center (T-17-020) least 1 minute and sepqrated by 1 or .more minutes Stony Brook, New York. This study was supported in part by a from successive episodes were printed out and regrant from Pfizer Laboratories, Inc. Manuscript received Octoviewed in a blinded fashion. Patient diaries were also ber 28,1987; revised manuscript received and accepted Decemkept with patients instructed to record their daily acber 10.1987. tivities on an hourly basis, except, of course, when
M
April 15, 1988
TABLE I
Clinical,
Anglographic
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 61
909
and Holter Findings Holter Monitoring Nifedipine
Pretreatment Narrowed
CA
Pt
Right
LAD
LC
MI
lschemic Episodes (n)
1 2 3 4 5 6 7 8 9 10 11 12
+ + + 0 + + + 3 + 0 + +
+ 0 + + + + 0 + + + + +
+ 0 0 + + + 0 0 + 0 + +
0 0 +(A) +(A) 0 +(I) 0 0 0 0 +(A) 0
11 6 4 6 3 17 4 0 6 4 5 6
Duration of lschemic Episodes (min)
asleep. After giving informed consent, each patient was monitored for 48 hours consecutively and then given nifedipine therapy, either 10 or 20 mg orally 3 times a day. (Two patients received the larger dose because they had previously required it for blood pressure control). Two to 3 days later, patients underwent repeat 48-hour Holter monitoring. Coronary arteriography was performed in a standard manner. A significant lesion was one that occluded a major coronary artery or one of its large branches by at least 70%. Ah 22 patients were men aged 42 to 67 years. Three patients had prior Q-wave myocardial infarction (1 was unrecognized], and 1 patient had a prior non-Qwave infarction. The site of the infarctions and vessel stenoses on coronary arteriography is listed in Table I. Six of the 12 patients had 3-vessel disease. During the initial 796 hours of monitoring there were 80 episodes of silent ischemia. The number ranged from 3 to 17 (Table I). Total duration was 2,487 minutes with a range of 14 to 699 minutes. Heart rate at onset of ST depression ranged from 60 to 150 beats/ min with a mean of 88 f 8. As recorded in the diaries, activity during these episodes was usually not related to heavy exertion, A circadian variation was found: 32 of the 80 episodes (40%) occurred in the 6 A.M. to 22 noon time period. The total number of ischemic episodes decreased to 37 (p
lschemic Episodes (n)
Duration of lschemic Episodes (min)
4 4 1 1 4 5 1 0 6 7 0 4
143 144 2 10 21 59 2 0 55 177 0 2
699 153 I5 53 39 120 14 40 37 197 52 68
A = anterior: CA = coronarv artery:_. I = inferior: LAD = left anterior circumflex coronary artery; MI = myocardial infarction.
TABLE II
Treatment
descending
coronary
Effect of Treatment
artery: LC = left
on Hotter Findings
Pretreatment lschemic episodes (n) Duration of ischemic episodes (mitt) Heart rate at onset of episodes (beatsjmin) Episodes occurring between 6 A.M. and 12 noon (%) NS = difference
During Nifedipine Administration
p Value
80
37
1,487
625
<0.05
a7
88
NS
40
42
NS
not significant.
To date, 3 studies of asymptomatic patients with coronary artery disease and silent myocardial ischemia out-of-hospital have been published.s-*O Whether these patients should be treated and if so, with what agents, is unclear because pertinent prognostic data are limited. What studies are available show that prognosis in asymptomatic coronary populations with silent ischemia on exercise testing [with or without prior infarctions] appears to be related to the extent of vessel disease and the degree of left ventricular dysfunction. Certainly, if one were going to treat an asymptomatic population with antiischemic drugs, the subgroup of high-risk patients with 3-vessel disease and moderate left ventricular dysfunction would seem best suited for such trials (although coronary artery surgery is also an option in these patients). But what agents-or combinations of agents-should one choose? Choice of drugs can be empiric (based on antianginal experience) or can depend on the results of pilot studies with asymptomatic patients. In our pilot study, we used nifedipine, a calcium antagonist with well-documented coronary vasodilatory properties, because increased vasoconstrictor tone as a contributing mechanism to silent ischemia has been suggested by (1) the lower
910
BRIEF REPORTS
than expected heart rates observed during many silent ischemic episodes and (2) the relative infrequency of episodes related to strenuous exertion. In the present study we used standard doses of the drugs and no attempt was made to titrate to higher levels. One of the warnings in interpreting our study data is day-to-day variability of ischemic episodes. This is especially important since this was not a randomized placebo-controlled trial. Preliminary studies by Deanfield et aliz suggest that for a trial of this size, one would need to show at least a 50% decrease in ischemic episodes before one could attribute the reduction to therapeutic agents. In our study, this level was achieved. Further, despite the use of just 1 drug at low doses, 9 of the 12 patients had marked improvement in both ischemic frequency and duration. Our reduction in ischemic frequency and duration is comparable to that achieved by Imperi et alIf using low dose metoprolol(50 mg 2 times daily) although the mechanisms of action of these 2 drugs are obviously different. Even after treatment, we found the percentage of ischemic activity was still highest from 6 A.M. to 12 noon. This was also true in the study by Imperi et al. In summary, even in standard dosages, nifedipine was effective in reducing the frequency and duration of silent myocardial ischemia in our patient population. Based on this initial pilot study, it would appear reasonable to consider nifedipine for testing in large scale, randomized, placebo-controlled studies of asymptomatic patients with silent ischemia. (If higher doses are used, however, they probably should be combined with /3 blockers to reduce reflex tachycardia). These trials could be designed to explore not only
Relation of left Ventricular Free Wall Rupture in Acute Myocardial Infarction to Forced Immobilization CHRISTIAN TORP-PEDERSEN, MD FRANK STEENSGAARD HANSEN, MD ASGER PEDERSEN, MD 1 eft ventricular (LV] free wall rupture occurs in approximately 10% of fatal acute myocardial infarctions (AMI).l In 1 report2 73% of the deaths associated with myocardial infarcts among institutionalized psychotic patients were due to LV rupture. This raised the possibility of a relation between physical activity and LV rupture. In a later report3 no difference was observed between psychotic and nonpsychotic patients at the same hospital. At present it is unclear whether physical activity is a risk factor for LV rupture in myocardial infarcts. We studied 7,009 consecutive cases of AM1 for a possible relation between mobilization and LV rupture. From the Department of Cardiology, Glostrup County Hospital, DK2600 Glostrup, Denmark. Manuscript received May 14.1987; revised manuscript received and accepted November 24,1987.
the therapeutic benefits of antiischemic drugs, but also the prognostic implications of treating ischemic episodes-whether they are painful or not. 1. Schang S]. Pepine CJ. Transient asymptomatic S-T depression during daily activity. Am J Cardiol 1977;39:396-40.2. 2. Deanfield JE,Shea M, Ribiero P, deLandsheere CM, Wilson RA. Horlock P, Selwyn AP. Transient ST-segmentdepression as a marker of myocardial ischemia during doily life. Am r Cardiol 1984;54:1195-1200. 3. Gottlieb SO, Weisfeldt ML, Quyang P, Mellits ED, Gerstenblith G. Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med 1986;314:1214-1219. 4. Cecchi AC, Dovellini EV, Marchi F, Pucci P, Santoro GM, Fazzini PF. Silent myocardiol ischemia during ambulatory electrocardiographic monitoring in patients with effort angina. JACC 1983;1:934-939. 5. Johnson SM, Mauritson DR. Willerson IT, Hills LD. A controlled trial of verapamil for Prinzmetal’s variant angina. N Engl J Med 1981;304:862868. 6. Quyyumi AA, Wright C, Mockus L, Shackell M, Sutton GC. Fox KM. Effects of combined alpha and beta adrenoceptor blockade in patients with angina pectods: a double blind study comparing Jabetalol with placebo. Br Heart [ 1985:53:47-52. 7. Gottlieb SO, Weisfeldt ML, Ouyang P, Achuff SC, Baughman KL, Trail1 TA, Brinker JA. Shapiro EP, Chandra N, Mellits ED, Townsend SN, Gerstenblith G. Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized. double-blind, placebo-controlled trial. Circulation 1986;73:331-337. 6. Campbell S. Barry J,Rebecca GS, Rocco MB, Nable EG, Wayne RR, Selwyn AP. Active transient myocardial ischemia during daily life in asymptomatic patients with positive exercise tests and coronary artery disease. Am 1 Cardiol 1986;57:1010-1016, 9. Coy KM, Imperi GA, Lambert CR, Pepine CJ. Silent myocordial ischemia during daily activities in asymptomatic men with positive exercise test responses. Am J Cardiol 1987;59:45-49. 10. Cohn PF, Lawson WE. Characteristics of silent myocardial ischemia during out-of-hospital activities in asymptomatic ongiographically documented coronary artery disease. Am J Cardiol 1987;59:746-749. 11. Imperi GA, Lambert CR, Coy K, Lopez L. Pepine CJ. Effects of titrated beta blockade (metoprolol] on silent myocardial ischemia in ambulatory patients with coronary artery disease. Am J Cardiol 1987;60:519-524. 12. Deanfield JE, Selwyn AP, He&y MJ. Variability of “stable angina” revealed by ST Holter monitoring: implications for clinical investigation (abstr). Circulation 1986;74(suppJII):40.
GJostrup County Hospital serves a well-defined urban and suburban area in Copenhagen, Denmark, with a population between 250,000 and 350,000. The coronary care unit receives all cardiac emergencies in the region. AMI is rarely treated at home. We have analyzed all cases of AMI admitted during the period 1959 to 1983. From 1959 to 2977 the diagnosis of AM1 was based strictly on the World Health Organization criteria.4 After 2977 a transient increase in serum JeveJsof the heart-specific creatine kinase isoenzyme in patients with a supposed onset of AMI within the preceding 36 hours was considered a prerequisite for the diagnosis. In a study from this department5 positive and negative predictive values of the transient increases in creatine kinase isoenzyme were 0.98 and 1.00 compared with the World Health Organization criteria. AM1 was assumed to take place at the onset oj severe chest pain. This time was well defined in all cases of LV rupture but 6. In all patients with LV rupture who survived more than a few hours after admittance, increased levels of creatine kinase isoenzyme or aspartate aminotransferase were demonstrated. In no case did autopsy indicate that the infarct was older than estimated by the onset of chest pain. Postmortem examination was performed routinely in all patients who died from known or suspected AMI. Data were available in 91% of fatal cases. The