Epilepsia, 17:ll-14,1976 Raven Press, New York
Ischemic Heart Disease in Patients with Epilepsy John F. Annegers, Lila R. Elveback, Darwin R. Labarthe, and W. Allen Hauser Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901
(Received October 1 5 , 1 9 7 5 ) with respect to the occurrence of fatal and nonfatal IHD.
INTRODUCTION Several recent reports have suggested that patients with epilepsy, particularly those on long-term anticonvulsant medication, may be at less than expected risk of ischemic heart disease (IHD) or sudden cardiac death. Two mechanisms have been Proposed to account for this postulated relationship. First, Linden has proposed an relationship with vitamin D levels as an explanation (1975). This argument is based On a report of lower than usual levels of vitamin D metabolites in patients on long-term anticonvulsant therapy (Hausslert 1974) and a reported ation between high levels of vitamin D consumption and occurrence of myocardial infarction (Linden, 19T4)* Second, Cooper (1974) has suggested that diphenylhydantoin, through “me mechanism* may have an antiarrhythmic effect and therefore may reduce the risks of myocardial infarction and sudden cardiac death. These speculations are of interest, but t o date no data have been presented to demonOccurrence Of IHD in that the patients with is less than expected. We report here Our study Of a cohort of patients with epilepsy in Rochester, Mimesota, between 1935 and 1970, undertaken to determine if the experience of these patients differed from that of the community as a whole
K~~ words: Ischemic heart disease conuulsant therapy - Epilepsy
-
~
METHODS Information pertaining to persons with diagnosed epilepsy was readily available from the data collected during a study of convulsive disorders in Rochester, Minnesota (Hauser and Kurland, 1975). There were 516 local residents with newly diagnosed epilepsy from 1935 to 1967. Among these, 99% were followed until either death or 1970. Three hundred ten of these were followed for period after they reached 30 years of age. The occurrence of fatal and nonfatal IHD was determined by detailed review of the records of these patients, on the basis of criteria similar $0 those employed in a previous study of IHD in this community (Oxman, unpublished). The expected numbers of new fatal nonfatal of IHD among using the these 310 patients were age- and sex-specific incidence and mortality rates derived from the prior These calculations were based on the number of age-specific person-years of follow-up from the tirne of diagnosis of epilepsy to the date of last follow-up for each individual subject. The observed numbers of events were then pared to those expected. The date of diagnosis of epilepsy also represents the initiation of anticonvulsant cation in most cases. Approximately 70% of the total person-years of observation for this cohort to ~ is ~believed i - represent current use of anticonvulsant medications.
11
J. F. ANNEGERS ET AL.
12
(observed = 12, expected = 6.1), whereas there was little difference for those over age 70 There were 25 new cases of IHD and 20 (observed = 8, expected = 9.6). However, the deaths resulting from IHD during the period of numbers of events in such subgroups are too observation following the diagnosis of epilepsy small to warrant strong conclusions. (Table 1). For 1 5 subjects, both the first The observed incidence of IHD exceeded diagnosis of IHD and death due to IHD that expected in 8 of the 1 0 age-sex subgroups occurred during this period. (These 1 5 cases are shown in Table 2. Overall, 25 cases were counted both among IHD deaths and among observed where only 15.7 were expected, a new IHD, fatal and nonfatal. There were 1 0 result of borderline significance (p = 0.05). (It additional new cases still alive, or dead of other should be noted that the groups at risk of new causes, at last follow-up.) events and of IHD deaths differ, since the latter For completeness, Table 1 also presents data includes cases with prior IHD diagnoses.) on IHD diagnosed before the diagnosis of All but 2 of the 30 total cases of interest epilepsy. There were 5 such subjects who died were prescribed anticonvulsant medication at of IHD during the period of follow-up after the some time. The anticonvulsant status of each diagnosis of epilepsy. Three additional subjects case at the time of the IHD event, as far as is with IHD before epilepsy remained alive or died known, is presented in Table 3. Most of the of other causes during the follow-up period. It patients had been prescribed barbiturates or should be noted that the total number of cases diphenylhydantoin near the time of onset o r of interest is 30, combining all new IHD with death. However, in many cases, medication the 5 deaths among IHD cases already diag- status at the actual time of the event could not nosed. The initial manifestation of IHD in the be established. The extent and type of anticon25 new cases was angina pectoris in 5, myo- vulsant usage in the group of IHD cases was cardial infarction in 13, and sudden death in 7. similar to that of the epilepsy group as a whole. A search was made for possible subgroups of Among the 20 deaths, 15 came to autopsy; a myocardial infarction was confirmed in all 1 5 the total cohort which might account for a disproportionate share of the IHD occurrence. cases. The observed and expected numbers of IHD One suspected group consisted of those whose events are compared in Table 2. Altogether, 20 convulsive disorder was considered to be due to deaths attributed to IHD were observed, where- vascular conditions or, specifically, to a cerebral as 15.7 were expected on the basis of the age vascular accident. Among 28 such cases, there and sex composition of the 2,667 person-years were 3 new IHD events observed (against 1.7 of observation. The mortality observed in those expected) and 2 deaths (2.6 expected). The under age 70 was greater than that expected possible influence of generalized tonic-clonic RESULTS
TABLE 1. Cases o f IHD identified in 3 1 0 patients with epilepsy, Rochester, Minnesota, 1935-19 70 Status at last follow-ur, Total Alive or dead from Initial manifestation number other causes IHD deaths Cases of IHD 5 diagnosed Angina pectoris afterthe Myocardial infarction 1 3 diagnosis of Sudden death 7 epilepsy Subtotal 25 Cases of IHD 4 diagnosed Angina pectoris before the Myocardial infarction 4 diagnosis of Subtotal 8 epilepsy Total 33
New IHD, fatal and nonfatal
2 8 0
3 5 7
5 13 7
10
15
25
2 1
2 3
3 -
5 -
-
13
20
25
IHD IN EPILEPTICS
13
TABLE 2. Observed and expected incidence and mortality from ischemic heart disease among 5 1 6 cases o f epilepsy, Rochester, Minnesota, 1935-1970 Age Males 30-39 40-49 50-59 60-69 70 + Subtotal Females 30-39 40-49 50-59 60-69 70 + Subtotal Total
Person-years at risk Per 100,00O/year New and nonfatal IHD IHD deaths Incidence Mortality Incidence Mortality Expected Observed Expected Observed 354 303 209 143 136
362 303 212 161 154
76 430 1291 2166 1857
30 204 570 1464 3563
-
-
534 363 218 192 210
534 364 220 231 226
-
-
-
-
-
-
-
-
9 77 319 930 1087
-
7 33 108 586 1056
seizures was examined by dividing the cohort into groups of subjects with and without generalized seizures (Table 4). N o clear difference appeared. Neither age at onset of seizures nor classification of seizures could be identified as factors which influenced the incidence of IHD. In all of these subgroup comparisons, the numbers of subjects at risk and expected values were quite small. The survivorship of IHD cases with epilepsy was compared to that of all IHD patients, based on the previous study already cited (Oxman, unpublished) The 3- and 5-year survivorship of IHD cases was similar to the experience expected for the total group of IHD cases in the community, irrespective of the presence of epilepsy .
CONCLUSION Our data do not show a decreased incidence of IHD among patients with epilepsy, as has been postulated by others; nor were we able to identify subgroups of our epilepsy patients at exceptionally low or high risk of IHD. However, the expected number of IHD cases became very small when our cohort was subdivided, so that at best only very large differences could have been detected in these subgroup analyses.
0.3 1.3 2.7 3.1 2.5
2 2 3 4 4
0.1 0.6 1.2 2.4 5.5
1 3 1 4 5
9.9
15
9.8
14
0.1 0.3 0.7 1.8 2.3
0 1 3 4 2
0.0 0.1 0.2 1.4 4.1
0
5.2 -
10 -
5.8 -
6 -
15.1
25
15.6
1 1 1 3
20
Finally, survivorship of epilepsy cases after the initial manifestation of IHD was comparable to that expected among all IHD cases. It is possible that factors other than anticonvulsant medications are associated with epilepsy and contribute to an increased risk of IHD, which negates any hypothetical protective effect of these drugs; our data do not deal with this issue. At present, we can only conclude that this investigation of IHD occurrence among a cohort of patients with epilepsy shows no evidence of reduced risk in relation to that of the community at large.
TABLE 3. Anticonvulsants and ischemic heart disease, Rochester, Minnesota, 1935-1 9 7 0 Anticonvulsant medication Diphenylhydantoin (DW DPH and barbiturate Barbiturate Possible DPH Possible DPH and barbiturate Possible barbiturate None Unknown Total
New IHD, fatal IHD or nonfatal death 3
1
5 6 1 5
2 3 2 5
0 4 1
2 4 1
30
25
J. F. ANNEGERS ET AL.
14
numbers of ischemic heart disease incidence and mortality cases were 25 and 15, respectively, relative to corresponding expected values of 15.0 and 15.7 new and fatal events. The use of New IHD, fatal and nonfatal IHD deaths anticonvulsant medications did not appear to Type of seizure ObEXObEX- influence the rates of ischemic heart disease history served pected served pected among the patients with epilepsy. Subgroups of the epilepsy patients, by etiology and types of With genepilepsy, were not found to account for a eralized disproportionate share of the ischemic heart 17 10.7 16 11.5 seizures disease. The survivorship of epilepsy patients Without after the initial manifestations of ischemic heart generalized disease was comparable to that expected among 8 4.3 4 4.2 all ischemic heart disease patients. seizures TABLE 4. Generalized seizures and ischemic heart disease, males and females combined, Rochester, Minnesota, 1935-1 9 7 0 ~
~
REFERENCES
SUMMARY It has been suggested that patients with epilepsy and particularly those on long-term anticonvulsant medication may have a lower than expected risk of ischemic heart disease. The records of a cohort of patients with epilepsy in Rochester, Minnesota were reviewed to ascertain their rates of occurrence of ischemic heart disease. The results did not show any relative decrease in the incidence or mortality rates due to ischemic heart disease among men or women with epilepsy. The
Cooper, I. Personal communication, 1974. Hauser, WA and Kurland, LT. The epidemiology of epilepsy in Rochester, Minnesota, 1 9 3 5 through 1967. Epilepsiu 16:l-66, 1975.
Haussler, MR. Vitamin D: Mode of action and biomedical applications. Nutr Rev 32:257, 1974.
Linden, V. Vitamin D and myocardial infarction. Br Med J 3:647, 1974. Linden, V. Myocardial infarction in epileptics (letter to ,editor). Br Med J 2:87, 1975. Oxman, HA. Ischemic heart disease in Rochester, Minnesota, 1945-1969. Unpublished.
Ischemic Heart Disease in Patients with Epilepsy John F. Annegers, Lila R. Elveback, Darwin R. Labarthe, and W. Allen Hauser Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901
(Received October 1 5 , 1 9 7 5 ) with respect to the occurrence of fatal and nonfatal IHD.
INTRODUCTION Several recent reports have suggested that patients with epilepsy, particularly those on long-term anticonvulsant medication, may be at less than expected risk of ischemic heart disease (IHD) or sudden cardiac death. Two mechanisms have been Proposed to account for this postulated relationship. First, Linden has proposed an relationship with vitamin D levels as an explanation (1975). This argument is based On a report of lower than usual levels of vitamin D metabolites in patients on long-term anticonvulsant therapy (Hausslert 1974) and a reported ation between high levels of vitamin D consumption and occurrence of myocardial infarction (Linden, 19T4)* Second, Cooper (1974) has suggested that diphenylhydantoin, through “me mechanism* may have an antiarrhythmic effect and therefore may reduce the risks of myocardial infarction and sudden cardiac death. These speculations are of interest, but t o date no data have been presented to demonOccurrence Of IHD in that the patients with is less than expected. We report here Our study Of a cohort of patients with epilepsy in Rochester, Mimesota, between 1935 and 1970, undertaken to determine if the experience of these patients differed from that of the community as a whole
K~~ words: Ischemic heart disease conuulsant therapy - Epilepsy
-
~
METHODS Information pertaining to persons with diagnosed epilepsy was readily available from the data collected during a study of convulsive disorders in Rochester, Minnesota (Hauser and Kurland, 1975). There were 516 local residents with newly diagnosed epilepsy from 1935 to 1967. Among these, 99% were followed until either death or 1970. Three hundred ten of these were followed for period after they reached 30 years of age. The occurrence of fatal and nonfatal IHD was determined by detailed review of the records of these patients, on the basis of criteria similar $0 those employed in a previous study of IHD in this community (Oxman, unpublished). The expected numbers of new fatal nonfatal of IHD among using the these 310 patients were age- and sex-specific incidence and mortality rates derived from the prior These calculations were based on the number of age-specific person-years of follow-up from the tirne of diagnosis of epilepsy to the date of last follow-up for each individual subject. The observed numbers of events were then pared to those expected. The date of diagnosis of epilepsy also represents the initiation of anticonvulsant cation in most cases. Approximately 70% of the total person-years of observation for this cohort to ~ is ~believed i - represent current use of anticonvulsant medications.
11
J. F. ANNEGERS ET AL.
12
(observed = 12, expected = 6.1), whereas there was little difference for those over age 70 There were 25 new cases of IHD and 20 (observed = 8, expected = 9.6). However, the deaths resulting from IHD during the period of numbers of events in such subgroups are too observation following the diagnosis of epilepsy small to warrant strong conclusions. (Table 1). For 1 5 subjects, both the first The observed incidence of IHD exceeded diagnosis of IHD and death due to IHD that expected in 8 of the 1 0 age-sex subgroups occurred during this period. (These 1 5 cases are shown in Table 2. Overall, 25 cases were counted both among IHD deaths and among observed where only 15.7 were expected, a new IHD, fatal and nonfatal. There were 1 0 result of borderline significance (p = 0.05). (It additional new cases still alive, or dead of other should be noted that the groups at risk of new causes, at last follow-up.) events and of IHD deaths differ, since the latter For completeness, Table 1 also presents data includes cases with prior IHD diagnoses.) on IHD diagnosed before the diagnosis of All but 2 of the 30 total cases of interest epilepsy. There were 5 such subjects who died were prescribed anticonvulsant medication at of IHD during the period of follow-up after the some time. The anticonvulsant status of each diagnosis of epilepsy. Three additional subjects case at the time of the IHD event, as far as is with IHD before epilepsy remained alive or died known, is presented in Table 3. Most of the of other causes during the follow-up period. It patients had been prescribed barbiturates or should be noted that the total number of cases diphenylhydantoin near the time of onset o r of interest is 30, combining all new IHD with death. However, in many cases, medication the 5 deaths among IHD cases already diag- status at the actual time of the event could not nosed. The initial manifestation of IHD in the be established. The extent and type of anticon25 new cases was angina pectoris in 5, myo- vulsant usage in the group of IHD cases was cardial infarction in 13, and sudden death in 7. similar to that of the epilepsy group as a whole. A search was made for possible subgroups of Among the 20 deaths, 15 came to autopsy; a myocardial infarction was confirmed in all 1 5 the total cohort which might account for a disproportionate share of the IHD occurrence. cases. The observed and expected numbers of IHD One suspected group consisted of those whose events are compared in Table 2. Altogether, 20 convulsive disorder was considered to be due to deaths attributed to IHD were observed, where- vascular conditions or, specifically, to a cerebral as 15.7 were expected on the basis of the age vascular accident. Among 28 such cases, there and sex composition of the 2,667 person-years were 3 new IHD events observed (against 1.7 of observation. The mortality observed in those expected) and 2 deaths (2.6 expected). The under age 70 was greater than that expected possible influence of generalized tonic-clonic RESULTS
TABLE 1. Cases o f IHD identified in 3 1 0 patients with epilepsy, Rochester, Minnesota, 1935-19 70 Status at last follow-ur, Total Alive or dead from Initial manifestation number other causes IHD deaths Cases of IHD 5 diagnosed Angina pectoris afterthe Myocardial infarction 1 3 diagnosis of Sudden death 7 epilepsy Subtotal 25 Cases of IHD 4 diagnosed Angina pectoris before the Myocardial infarction 4 diagnosis of Subtotal 8 epilepsy Total 33
New IHD, fatal and nonfatal
2 8 0
3 5 7
5 13 7
10
15
25
2 1
2 3
3 -
5 -
-
13
20
25
IHD IN EPILEPTICS
13
TABLE 2. Observed and expected incidence and mortality from ischemic heart disease among 5 1 6 cases o f epilepsy, Rochester, Minnesota, 1935-1970 Age Males 30-39 40-49 50-59 60-69 70 + Subtotal Females 30-39 40-49 50-59 60-69 70 + Subtotal Total
Person-years at risk Per 100,00O/year New and nonfatal IHD IHD deaths Incidence Mortality Incidence Mortality Expected Observed Expected Observed 354 303 209 143 136
362 303 212 161 154
76 430 1291 2166 1857
30 204 570 1464 3563
-
-
534 363 218 192 210
534 364 220 231 226
-
-
-
-
-
-
-
-
9 77 319 930 1087
-
7 33 108 586 1056
seizures was examined by dividing the cohort into groups of subjects with and without generalized seizures (Table 4). N o clear difference appeared. Neither age at onset of seizures nor classification of seizures could be identified as factors which influenced the incidence of IHD. In all of these subgroup comparisons, the numbers of subjects at risk and expected values were quite small. The survivorship of IHD cases with epilepsy was compared to that of all IHD patients, based on the previous study already cited (Oxman, unpublished) The 3- and 5-year survivorship of IHD cases was similar to the experience expected for the total group of IHD cases in the community, irrespective of the presence of epilepsy .
CONCLUSION Our data do not show a decreased incidence of IHD among patients with epilepsy, as has been postulated by others; nor were we able to identify subgroups of our epilepsy patients at exceptionally low or high risk of IHD. However, the expected number of IHD cases became very small when our cohort was subdivided, so that at best only very large differences could have been detected in these subgroup analyses.
0.3 1.3 2.7 3.1 2.5
2 2 3 4 4
0.1 0.6 1.2 2.4 5.5
1 3 1 4 5
9.9
15
9.8
14
0.1 0.3 0.7 1.8 2.3
0 1 3 4 2
0.0 0.1 0.2 1.4 4.1
0
5.2 -
10 -
5.8 -
6 -
15.1
25
15.6
1 1 1 3
20
Finally, survivorship of epilepsy cases after the initial manifestation of IHD was comparable to that expected among all IHD cases. It is possible that factors other than anticonvulsant medications are associated with epilepsy and contribute to an increased risk of IHD, which negates any hypothetical protective effect of these drugs; our data do not deal with this issue. At present, we can only conclude that this investigation of IHD occurrence among a cohort of patients with epilepsy shows no evidence of reduced risk in relation to that of the community at large.
TABLE 3. Anticonvulsants and ischemic heart disease, Rochester, Minnesota, 1935-1 9 7 0 Anticonvulsant medication Diphenylhydantoin (DW DPH and barbiturate Barbiturate Possible DPH Possible DPH and barbiturate Possible barbiturate None Unknown Total
New IHD, fatal IHD or nonfatal death 3
1
5 6 1 5
2 3 2 5
0 4 1
2 4 1
30
25
J. F. ANNEGERS ET AL.
14
numbers of ischemic heart disease incidence and mortality cases were 25 and 15, respectively, relative to corresponding expected values of 15.0 and 15.7 new and fatal events. The use of New IHD, fatal and nonfatal IHD deaths anticonvulsant medications did not appear to Type of seizure ObEXObEX- influence the rates of ischemic heart disease history served pected served pected among the patients with epilepsy. Subgroups of the epilepsy patients, by etiology and types of With genepilepsy, were not found to account for a eralized disproportionate share of the ischemic heart 17 10.7 16 11.5 seizures disease. The survivorship of epilepsy patients Without after the initial manifestations of ischemic heart generalized disease was comparable to that expected among 8 4.3 4 4.2 all ischemic heart disease patients. seizures TABLE 4. Generalized seizures and ischemic heart disease, males and females combined, Rochester, Minnesota, 1935-1 9 7 0 ~
~
REFERENCES
SUMMARY It has been suggested that patients with epilepsy and particularly those on long-term anticonvulsant medication may have a lower than expected risk of ischemic heart disease. The records of a cohort of patients with epilepsy in Rochester, Minnesota were reviewed to ascertain their rates of occurrence of ischemic heart disease. The results did not show any relative decrease in the incidence or mortality rates due to ischemic heart disease among men or women with epilepsy. The
Cooper, I. Personal communication, 1974. Hauser, WA and Kurland, LT. The epidemiology of epilepsy in Rochester, Minnesota, 1 9 3 5 through 1967. Epilepsiu 16:l-66, 1975.
Haussler, MR. Vitamin D: Mode of action and biomedical applications. Nutr Rev 32:257, 1974.
Linden, V. Vitamin D and myocardial infarction. Br Med J 3:647, 1974. Linden, V. Myocardial infarction in epileptics (letter to ,editor). Br Med J 2:87, 1975. Oxman, HA. Ischemic heart disease in Rochester, Minnesota, 1945-1969. Unpublished.
