Editorial Comment
What do we know about the risks of stopping antihypertensive treatment? Bo Carlberg
See original paper on page 1478
I
n this issue of Journal of Hypertension, Becket et al. [1] report the results from subgroup analyses in HYVET (Hypertension in the Very Old Trial). HYVET is the largest randomized controlled cardiovascular outcome trial in patients aged at least 80 years in which antihypertensive treatment was compared with placebo [2]. During treatment, the mean blood pressure achieved was 144/78 mmHg in the intervention group compared with 159/84 mmHg in the placebo group. The study was stopped prematurely after 2 years of follow-up, as the total mortality was higher in the placebo group than in the active treatment group. Interestingly, a similar trial – the STOP-Hypertension (Swedish Trial in Old Patients with Hypertension) [3] – was also stopped prematurely because of increased mortality in the placebo group. Here, 70–84-year-old patients with hypertension were randomized to antihypertensive treatment or placebo. However, a systematic review of hypertension treatment in patients aged at least 80 years, in which HYVET was included, found that antihypertensive
therapy did not reduce the risk for total mortality or cardiovascular mortality compared with placebo [4]. The risk for stroke was, however, significantly reduced with treatment (risk ratio 0.66, 95% confidence interval 0.52–0.83) One subgroup analysis of HYVET raises questions about what we really know about treating hypertension in the very old. In HYVET, two out of three patients had been previously treated for hypertension. Thus, in two-thirds of the patients, in the placebo group, what HYVET really tested was the effect of stopping antihypertensive treatment. Also, in STOP-Hypertension, about half of the patients were previously treated before they were randomized to placebo or active treatment. Table 1 summarizes that any effect on total mortality and cardiovascular mortality in HYVET was only evident in the previously treated subgroup. It is not clear how these results should be interpreted, as there was no effect on mortality in the treatment-naive group. Unfortunately, the authors did not analyse the interactions between the treatment effects in these groups, and it cannot be
TABLE 1. Hazard ratios for treatment with indapamide with or without perindopril compared with placebo Total HYVET antihypertensive treatment vs. placebo n ¼ 3845 hazard ratio (95% confidence interval) Total mortality Cardiovascular death All cardiovascular events Stroke Heart failure Myocardial infarction
0.79 0.77 0.66 0.70 0.36 0.72
(0.65–0.95) (0.60–1.01) (0.53–0.82) (0.49–1.01) (0.22–0.58) (0.30–1.70)
Subgroup starting treatment vs. no treatment (placebo) n ¼ 1359 hazard ratio (95% confidence interval) 0.95 0.94 0.69 0.73 0.28
(0.69–1.31) (0.61–1.47) (0.48–0.99) (0.39–1.36) (0.12–0.65) ?
Subgroup continuing treatment vs. stopping treatment (placebo) n ¼ 2486 hazard ratio (95% confidence interval) 0.71 0.69 0.65 0.69 0.42
(0.56–0.90) (0.50–0.97) (0.50–0.86) (0.44–1.07) (0.23–0.76) ?
The first column includes data from whole HYVET population [2]. The second column shows data from patients without previous antihypertensive therapy. The third column shows data from patients previously treated for hypertension.
Journal of Hypertension 2014, 32:1400–1401 Department of Public Health and Clinical Medicine, Umea˚ University, Umea˚, Sweden Correspondence to Bo Carlberg, MD, PhD, Department of Public Health and Clinical Medicine, Umea˚ University, SE-901 87 Umea˚, Sweden. E-mail: [email protected] J Hypertens 32:1400–1401 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000200
1400
www.jhypertension.com
concluded that treatment did not have positive effects on mortality in the treatment-naive group. On the contrary, the overall study showed a significantly reduced mortality in the treatment group compared with placebo. The results from HYVET subgroup analyses raise a number of important questions. Is it dangerous to stop antihypertensive treatment in elderly? If it is dangerous to stop antihypertensive treatment in healthy elderly, is it more or less dangerous to do so in frail elderly? Volume 32 Number 7 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Risks of stopping antihypertensive treatment
Old patients often visit emergency departments with symptoms associated with hypotension. Also, many old patients suffer from side effects from drug treatment that is no longer needed. A common result from these consultations is a reduction of drug therapies. It is reasonable to think that this is a good practice, but what do we really know? We do have enough evidence for starting antihypertensive treatment in those over 80 years of age. However, what conclusions about specific hypertension treatment goals for the over-80 age group are possible to make, when much of the evidence from HYVET comes from stopping, not initiating treatment? We would need randomized controlled trials about stopping antihypertensive therapy in frail elderly before we can be confident that this is for the best of the patient. On the contrary, the ethical aspect of such studies would not be uncomplicated.
Journal of Hypertension
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Beckett N, Peters R, Leonetti G, Duggan J, Fagard R, Thijs L, et al. Subgroup and per-protocol analyses from the Hypertension in the Very Elderly Trial. J Hypertens 2014; 32:1478–1487. 2. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age, or older. N Engl J Med 2008; 358:1887–1898. 3. Dahlo¨f B, Lindholm LH, Hansson L, Scherste´n B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338:1281–1285. 4. Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst Rev 2009; CD000028.
www.jhypertension.com
1401
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
What do we know about the risks of stopping antihypertensive treatment? Bo Carlberg
See original paper on page 1478
I
n this issue of Journal of Hypertension, Becket et al. [1] report the results from subgroup analyses in HYVET (Hypertension in the Very Old Trial). HYVET is the largest randomized controlled cardiovascular outcome trial in patients aged at least 80 years in which antihypertensive treatment was compared with placebo [2]. During treatment, the mean blood pressure achieved was 144/78 mmHg in the intervention group compared with 159/84 mmHg in the placebo group. The study was stopped prematurely after 2 years of follow-up, as the total mortality was higher in the placebo group than in the active treatment group. Interestingly, a similar trial – the STOP-Hypertension (Swedish Trial in Old Patients with Hypertension) [3] – was also stopped prematurely because of increased mortality in the placebo group. Here, 70–84-year-old patients with hypertension were randomized to antihypertensive treatment or placebo. However, a systematic review of hypertension treatment in patients aged at least 80 years, in which HYVET was included, found that antihypertensive
therapy did not reduce the risk for total mortality or cardiovascular mortality compared with placebo [4]. The risk for stroke was, however, significantly reduced with treatment (risk ratio 0.66, 95% confidence interval 0.52–0.83) One subgroup analysis of HYVET raises questions about what we really know about treating hypertension in the very old. In HYVET, two out of three patients had been previously treated for hypertension. Thus, in two-thirds of the patients, in the placebo group, what HYVET really tested was the effect of stopping antihypertensive treatment. Also, in STOP-Hypertension, about half of the patients were previously treated before they were randomized to placebo or active treatment. Table 1 summarizes that any effect on total mortality and cardiovascular mortality in HYVET was only evident in the previously treated subgroup. It is not clear how these results should be interpreted, as there was no effect on mortality in the treatment-naive group. Unfortunately, the authors did not analyse the interactions between the treatment effects in these groups, and it cannot be
TABLE 1. Hazard ratios for treatment with indapamide with or without perindopril compared with placebo Total HYVET antihypertensive treatment vs. placebo n ¼ 3845 hazard ratio (95% confidence interval) Total mortality Cardiovascular death All cardiovascular events Stroke Heart failure Myocardial infarction
0.79 0.77 0.66 0.70 0.36 0.72
(0.65–0.95) (0.60–1.01) (0.53–0.82) (0.49–1.01) (0.22–0.58) (0.30–1.70)
Subgroup starting treatment vs. no treatment (placebo) n ¼ 1359 hazard ratio (95% confidence interval) 0.95 0.94 0.69 0.73 0.28
(0.69–1.31) (0.61–1.47) (0.48–0.99) (0.39–1.36) (0.12–0.65) ?
Subgroup continuing treatment vs. stopping treatment (placebo) n ¼ 2486 hazard ratio (95% confidence interval) 0.71 0.69 0.65 0.69 0.42
(0.56–0.90) (0.50–0.97) (0.50–0.86) (0.44–1.07) (0.23–0.76) ?
The first column includes data from whole HYVET population [2]. The second column shows data from patients without previous antihypertensive therapy. The third column shows data from patients previously treated for hypertension.
Journal of Hypertension 2014, 32:1400–1401 Department of Public Health and Clinical Medicine, Umea˚ University, Umea˚, Sweden Correspondence to Bo Carlberg, MD, PhD, Department of Public Health and Clinical Medicine, Umea˚ University, SE-901 87 Umea˚, Sweden. E-mail: [email protected] J Hypertens 32:1400–1401 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000200
1400
www.jhypertension.com
concluded that treatment did not have positive effects on mortality in the treatment-naive group. On the contrary, the overall study showed a significantly reduced mortality in the treatment group compared with placebo. The results from HYVET subgroup analyses raise a number of important questions. Is it dangerous to stop antihypertensive treatment in elderly? If it is dangerous to stop antihypertensive treatment in healthy elderly, is it more or less dangerous to do so in frail elderly? Volume 32 Number 7 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Risks of stopping antihypertensive treatment
Old patients often visit emergency departments with symptoms associated with hypotension. Also, many old patients suffer from side effects from drug treatment that is no longer needed. A common result from these consultations is a reduction of drug therapies. It is reasonable to think that this is a good practice, but what do we really know? We do have enough evidence for starting antihypertensive treatment in those over 80 years of age. However, what conclusions about specific hypertension treatment goals for the over-80 age group are possible to make, when much of the evidence from HYVET comes from stopping, not initiating treatment? We would need randomized controlled trials about stopping antihypertensive therapy in frail elderly before we can be confident that this is for the best of the patient. On the contrary, the ethical aspect of such studies would not be uncomplicated.
Journal of Hypertension
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Beckett N, Peters R, Leonetti G, Duggan J, Fagard R, Thijs L, et al. Subgroup and per-protocol analyses from the Hypertension in the Very Elderly Trial. J Hypertens 2014; 32:1478–1487. 2. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age, or older. N Engl J Med 2008; 358:1887–1898. 3. Dahlo¨f B, Lindholm LH, Hansson L, Scherste´n B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991; 338:1281–1285. 4. Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst Rev 2009; CD000028.
www.jhypertension.com
1401
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
