Cardiovascular Risk After Discontinuation of HRT After MI
Cardiovascular Risk After Discontinuation of HRT After MI
A total of 44,099 women aged 40 or over on 1 January 1997 had a myocardial infarction in the period 1997 to 2008, but 10,494 of these women died during the first 30 days after discharge and were therefore excluded, as were the 71 women lost to follow-up (Figure 1). Among the remaining 33,534 women, 3322 (9.9%) were using HRT at the time of myocardial infarction, and these women constituted the population of this study. The number of reinfarctions during follow-up was 282 (8.5%), 357 (10.7%) women died of all causes, and 218 (6.6%) died of cardiovascular causes.
Most women used the combination of systemic oestrogen and progestogen (1100; 33.1%), followed by vaginal oestrogen (977, 29.4%) and systemic oestrogen alone (954, 28.7%). Only 291 (8.8%) women used HRT belonging to the category “other HRT” ( Table 2 ). Baseline characteristics of women using different categories of HRT were very different, as is evident from Table 2 and as we have previously found.
Analyses of discontinuation in the first 30-360 days after myocardial infarction showed an association between discontinuation of vaginal oestrogen and a decreased risk of reinfarction (hazard ratio 0.54, 95% confidence interval 0.34 to 0.86), as well as an insignificant association for discontinuation of systemic oestrogen (0.56, 0.28 to 1.11) and overall HRT (0.90, 0.68 to 1.19) ( Table 3 ). We also found a statistically insignificant increase in cardiovascular mortality (hazard ratio 1.39, 0.73 to 2.66, for discontinuation of systemic oestrogen; 1.15, 0.78 to 1.72, for vaginal oestrogen; and 1.21, 0.90 to 1.62, for overall HRT) and all cause mortality (hazard ratio 1.17, 0.70 to 1.94, for discontinuation of systemic oestrogen; 1.31, 0.95 to 1.83, for vaginal oestrogen; and 1.22, 0.97 to 1.53, for overall HRT)
When analysing the different durations of discontinuation, we found that discontinuation of overall HRT for 1-90 days was associated with an increased risk of cardiovascular mortality and all cause mortality but no increased risk of reinfarction (Figure 2). This increased risk was apparent for cardiovascular mortality only when discontinuation occurred in the period 30-90 days after discharge (hazard ratio 1.90, 1.15 to 3.12) and for all cause mortality in both the periods 30-90 days (1.58, 1.04 to 2.39) and 91-180 days after discharge (1.76, 1.08 to 2.87). For 1-90 days of discontinuation of systemic oestrogen alone, we found increased cardiovascular mortality (hazard ratio 6.14, 1.95 to 19.3) and all cause mortality (3.23, 1.30 to 8.07) during the first 30-90 days after discharge (Figure 2). Again, we found a statistically insignificant lower risk of reinfarction. For 1-90 days of discontinuation of vaginal oestrogen, we found a decreased risk of reinfarction during the first 30-90 days after discharge (hazard ratio 0.36, 0.16 to 0.82) (Figure 2). For all the above, the corresponding unadjusted incidence rates of continued and discontinued treatment were equivalent to the proportional hazard analyses ( Table 3 , Table 4 , Table 5 , and Table 6 ). For discontinuation of combinations of oestrogen and progestogen and for the category “other HRT,” calculations were limited owing to very few endpoints ( Table 3 , Figure 2).
(Enlarge Image)
Figure 2.
Hazard ratios (95% CI) for reinfarction, cardiovascular mortality, and all cause mortality for discontinuation of hormone replacement therapy (HRT) overall and HRT categories. Hazard ratios are for discontinuation with continued use as reference. Multivariable Cox proportional hazards analysis was adjusted for age group, year of myocardial infarction (MI), comorbidity (previous MI, revascularisation within 30 days of MI, cerebrovascular disease, congestive heart failure, malignancy, cardiac dysrhythmias, chronic renal failure, acute renal failure, diabetes with complications, pulmonary oedema, shock), concomitant drug use (β blockers, angiotensin converting enzyme inhibitors, statins, loop diuretics, clopidogrel, glucose lowering drugs), and income. No interactions were found or included in model
Table 7 and Table 8 show the results of the sensitivity analyses. The associations between discontinuation and the endpoints did not change significantly after inclusion of the first 30 days in the analyses or after postponement of the time of discontinuation by seven or 14 days.
To test whether the low risk of reinfarction after discontinuation of vaginal oestrogen found in both the first year and the first 30-90 days after myocardial infarction could be due to unmeasured confounding, we tried to estimate the hypothetical size of such an unmeasured confounder, assuming a 20% prevalence of an unmeasured confounder in the population and a prevalence of discontinuation of 20%. The results indicate that an unmeasured confounder would be very unevenly distributed between the groups and have a very strong association with continued treatment (Figure 3 and Figure 4). A confounder or combination of confounders that could decrease the risk of reinfarction from 1.00 to 0.54 for discontinuation in the first year after myocardial infarction would have to increase the risk fivefold (Figure 3) and thereby exceed the effects of any measured confounder in the study, such as diabetes or age 80 or over. However, to render the results statistically insignificant, a confounder would have to increase the risk only twofold. In the case of discontinuation of vaginal oestrogen in the first 30-90 days after myocardial infarction, a confounder would have to increase the risk less than twofold to make the result statistically insignificant (Figure 4).
(Enlarge Image)
Figure 3.
Required size of unmeasured confounder to fully explain decrease in risk from 1.00 to 0.54 (solid blue line) and to render results statistically insignificant (dashed red line), assuming prevalence of confounder of 20% in population and prevalence of discontinuation of 20%
(Enlarge Image)
Figure 4.
Required size of unmeasured confounder to fully explain decrease in risk from 1.00 to 0.41 (solid blue line) and to render results statistically insignificant (dashed red line), assuming prevalence of confounder of 20% in population and prevalence of discontinuation of 20%
Results
A total of 44,099 women aged 40 or over on 1 January 1997 had a myocardial infarction in the period 1997 to 2008, but 10,494 of these women died during the first 30 days after discharge and were therefore excluded, as were the 71 women lost to follow-up (Figure 1). Among the remaining 33,534 women, 3322 (9.9%) were using HRT at the time of myocardial infarction, and these women constituted the population of this study. The number of reinfarctions during follow-up was 282 (8.5%), 357 (10.7%) women died of all causes, and 218 (6.6%) died of cardiovascular causes.
Most women used the combination of systemic oestrogen and progestogen (1100; 33.1%), followed by vaginal oestrogen (977, 29.4%) and systemic oestrogen alone (954, 28.7%). Only 291 (8.8%) women used HRT belonging to the category “other HRT” ( Table 2 ). Baseline characteristics of women using different categories of HRT were very different, as is evident from Table 2 and as we have previously found.
Analyses of discontinuation in the first 30-360 days after myocardial infarction showed an association between discontinuation of vaginal oestrogen and a decreased risk of reinfarction (hazard ratio 0.54, 95% confidence interval 0.34 to 0.86), as well as an insignificant association for discontinuation of systemic oestrogen (0.56, 0.28 to 1.11) and overall HRT (0.90, 0.68 to 1.19) ( Table 3 ). We also found a statistically insignificant increase in cardiovascular mortality (hazard ratio 1.39, 0.73 to 2.66, for discontinuation of systemic oestrogen; 1.15, 0.78 to 1.72, for vaginal oestrogen; and 1.21, 0.90 to 1.62, for overall HRT) and all cause mortality (hazard ratio 1.17, 0.70 to 1.94, for discontinuation of systemic oestrogen; 1.31, 0.95 to 1.83, for vaginal oestrogen; and 1.22, 0.97 to 1.53, for overall HRT)
When analysing the different durations of discontinuation, we found that discontinuation of overall HRT for 1-90 days was associated with an increased risk of cardiovascular mortality and all cause mortality but no increased risk of reinfarction (Figure 2). This increased risk was apparent for cardiovascular mortality only when discontinuation occurred in the period 30-90 days after discharge (hazard ratio 1.90, 1.15 to 3.12) and for all cause mortality in both the periods 30-90 days (1.58, 1.04 to 2.39) and 91-180 days after discharge (1.76, 1.08 to 2.87). For 1-90 days of discontinuation of systemic oestrogen alone, we found increased cardiovascular mortality (hazard ratio 6.14, 1.95 to 19.3) and all cause mortality (3.23, 1.30 to 8.07) during the first 30-90 days after discharge (Figure 2). Again, we found a statistically insignificant lower risk of reinfarction. For 1-90 days of discontinuation of vaginal oestrogen, we found a decreased risk of reinfarction during the first 30-90 days after discharge (hazard ratio 0.36, 0.16 to 0.82) (Figure 2). For all the above, the corresponding unadjusted incidence rates of continued and discontinued treatment were equivalent to the proportional hazard analyses ( Table 3 , Table 4 , Table 5 , and Table 6 ). For discontinuation of combinations of oestrogen and progestogen and for the category “other HRT,” calculations were limited owing to very few endpoints ( Table 3 , Figure 2).
(Enlarge Image)
Figure 2.
Hazard ratios (95% CI) for reinfarction, cardiovascular mortality, and all cause mortality for discontinuation of hormone replacement therapy (HRT) overall and HRT categories. Hazard ratios are for discontinuation with continued use as reference. Multivariable Cox proportional hazards analysis was adjusted for age group, year of myocardial infarction (MI), comorbidity (previous MI, revascularisation within 30 days of MI, cerebrovascular disease, congestive heart failure, malignancy, cardiac dysrhythmias, chronic renal failure, acute renal failure, diabetes with complications, pulmonary oedema, shock), concomitant drug use (β blockers, angiotensin converting enzyme inhibitors, statins, loop diuretics, clopidogrel, glucose lowering drugs), and income. No interactions were found or included in model
Table 7 and Table 8 show the results of the sensitivity analyses. The associations between discontinuation and the endpoints did not change significantly after inclusion of the first 30 days in the analyses or after postponement of the time of discontinuation by seven or 14 days.
Unmeasured Confounding
To test whether the low risk of reinfarction after discontinuation of vaginal oestrogen found in both the first year and the first 30-90 days after myocardial infarction could be due to unmeasured confounding, we tried to estimate the hypothetical size of such an unmeasured confounder, assuming a 20% prevalence of an unmeasured confounder in the population and a prevalence of discontinuation of 20%. The results indicate that an unmeasured confounder would be very unevenly distributed between the groups and have a very strong association with continued treatment (Figure 3 and Figure 4). A confounder or combination of confounders that could decrease the risk of reinfarction from 1.00 to 0.54 for discontinuation in the first year after myocardial infarction would have to increase the risk fivefold (Figure 3) and thereby exceed the effects of any measured confounder in the study, such as diabetes or age 80 or over. However, to render the results statistically insignificant, a confounder would have to increase the risk only twofold. In the case of discontinuation of vaginal oestrogen in the first 30-90 days after myocardial infarction, a confounder would have to increase the risk less than twofold to make the result statistically insignificant (Figure 4).
(Enlarge Image)
Figure 3.
Required size of unmeasured confounder to fully explain decrease in risk from 1.00 to 0.54 (solid blue line) and to render results statistically insignificant (dashed red line), assuming prevalence of confounder of 20% in population and prevalence of discontinuation of 20%
(Enlarge Image)
Figure 4.
Required size of unmeasured confounder to fully explain decrease in risk from 1.00 to 0.41 (solid blue line) and to render results statistically insignificant (dashed red line), assuming prevalence of confounder of 20% in population and prevalence of discontinuation of 20%