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Insufficient reliable evidence about treating hypertensive emergencies
TREATMENT
Insufficient reliable evidence about treating hypertensive emergencies Abstracted from: Cherney D, Straus S. Management of patients with hypertensive urgencies and emergencies. A systematic review of the literature. J Gen Intern Med 2002; 17: 937^945.
BACKGROUND Many antihypertensive medications exist but there is little evidence on their relative e¡ectiveness in hypertensive emergencies (where endorgan damage has occurred) or urgencies (where there is an increased risk of short-term morbidity, but not end-organ damage). OBJECTIVE To assess the evidence for the relative e¡ectiveness of di¡erent antihypertensive regimens in reducing blood pressure to safe levels in hypertensive emergencies or urgencies. METHOD Systematic review. SEARCH STRATEGY MEDLINE, reference lists and the Cochrane Library were searched. Search date 2001. INCLUSION/EXCLUSION CRITERIA Randomised controlled trials; cohort studies; systematic reviews including studies with these designs; all-ornone studies (all patients died before the medication under test was available but now some survive using it, or, some died before but now none die), and outcomes research (description of e¡ectiveness in practice rather than in a trial situation). No language restrictions. Adults with hypertensive urgencies or emergencies. DATA ANALYSIS Narrative synthesis. Where available, number needed to treat (NNT) was calculated using the Mount Sinai Hospital Center for Evidence Based Medicine Statistics Calculator. MAIN OUTCOMES T|me required for drug to reduce blood pressure to target levels. MAIN RESULTS Hypertensive emergencies: One randomised controlled trial was identi¢ed, which found no signi¢cant di¡erence between captopril and nifedipine for reducing diastolic blood pressure below 120 mmHg and eliminating symptoms at 60 minutes (NNT for captopril v nifedipine 5, 95% CI; NNH 2 to NNT 5).Three other, poorer quality studies found that nifedipine
150
Evidence-based Cardiovascular Medicine (2003) 7,150 ^152 doi:10.1016/S1361-2611(03)00062-9
reduced blood pressure to target levels more quickly than nitroprusside (4.5 v 14.2 hours, po0.05), and found that urapidil was better than nitroprusside in reducing blood pressure to target levels within 90 minutes (NNT 12; 95% CI 5 to+40). Hypertensive urgencies: Fifteen studies were identi¢ed, 10 of which were randomised controlled trials. Findings were as follows: K
K
K
K
K
K
K
Nicardipine lowered blood pressure to target levels in more patients than placebo (65% v 22%, p = 0.002, NNT 2). Long-acting lacidipine was more e¡ective at controlling the blood pressure at 24 hours than nifedipine ( p = 0.001, NNT 2). Control of blood pressure was greater with urapidil than nifedipine after a single dose (92% v 70%, po0.04, NNT 5). Control of blood pressure was greater with nifedipine than clonidine (NNT 2). Enalaprilat was not signi¢cantly more e¡ective than placebo in people with moderate hypertension (diastolic blood pressure 100 to 144 mmHg) and was not signi¢cantly more e¡ective than furosemide in people with severe hypertension (diastolic blood pressure 115 to 130). Oral nifedipine was of similar e⁄cacy to oral labetolol or nitrendipine ( p40.05). Fenoldopam was of similar e⁄cacy to nitroprusside ( p40.05).
AUTHORS’ CONCLUSIONS Evidence about e¡ectiveness of antihypertensive agents in people with hypertensive emergencies or hypertensive urgencies is weak. Studies had small sample sizes and were heterogeneous in terms of patients, interventions and outcomes reported. Limited evidence suggests that urapidil is most e¡ective in emergencies. In urgencies, nicardipine; lacidipine; urapidil; nitroprusside or fenolodopam may be used, but not nifedipine. Sources offunding: Notspeci¢ed. Correspondence to: D Cherney, 50 Walmer Road, Apt107,Toronto, Ontario, M5R 2X4. Email: [email protected] Abstract provided by Bazian Ltd, London.
1361-2611/03/$ - see front matter & 2003 Elsevier Ltd. Allrights reserved.
Commentary Hypertensive emergencies and urgencies affect approximately 1% of all hypertensive patients. However, according to the recently published JNC VII guidelines for hypertension, there are more than 50 million hypertensive patients in the United States and up to 1 billion worldwide.1 Thus, hypertensive urgencies and emergencies are a common problem in the emergency room ^ up to 3% of all emergency visits. Unfortunately, there are few high-quality studies that address the problem of hypertensive emergencies and urgencies, and so most of the clinical management of hypertensive crises is based on clinical judgment rather than on evidence-based literature. The Cherney review2 has carefully assembled many of the better studies on hypertensive emergencies and urgencies from 1966 to 2001, but then attempts to clarify treatment options based on small studies with di¡erent inclusion criteria, treatments, and outcomes. The authors recognize the disparities between studies and appropriately include warnings throughout their review that the purpose of their study is ‘to show what is known and what is not known, about hypertensive urgencies and emergencies.’ Part of the problem of summarizing studies on hypertensive emergencies and urgencies is the lack of clear definitions. A hypertensive emergency is defined by JNC VI as a ‘rare situation that requires immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage,’ with the most common organ systems involved being the central nervous system, cardiovascular, pulmonary, renal, ophthalmologic, or the fetus in pregnancy.3 InTable 2 of the Cherney review, only four studies are categorized under hypertensive emergencies, and their inclusion criteria are markedly different, ranging from patients with evidence of end-organ damage, such as eye ground changes, to patients recruited with severe high blood pressure, with no explicit exclusion of end-organ damage. The authors themselves seem a bit discomfited by their concluding statement that urapidil has the most effective number needed to treat, since it was only used in a single study, and the result is not statistically significant. Also, the studies included do not address the more severe hypertensive emergencies, in which treatment is often driven by the specific end-organ affected. For instance, in the setting of an acute myocardial infarction with greatly elevated blood pressure, intravenous nitroglycerin might be preferred, whereas in the setting of an aortic dissection, a beta-blocker should be used before a nitrate is added in order to minimize wall stress. Fenoldapam, a dopamine-1 receptor agonist, might be preferred in the setting of worsening renal insufficiency in order to increase renal vasodilatation.4 In the setting of an acute stroke, clinicians should avoid rapid blood pressure reduction since cerebral damage can be worsened by ischemia.5 The definition of ‘hypertensive urgencies’ is most often described as severely elevated blood pressure with no evidence of target organ damage. However, there is no consensus on the threshold for ‘severe’ blood pressure elevation. The lack of consensus is seen inTable 3 of the review, where the included studies used different BP criteria, including a diastolic blood pressure (DBP) of110 ^140, DBP 4120, DBP116 ^139, or systolic blood pressure (SBP) 4 200 and/or DBP 4 110.The lack of a clear def|nition for urgent hypertension makes it a di⁄cult problem to treat. Since most of the patients presenting with severely elevated blood pressure have chronic essential hypertension, it is unclear how quickly their blood pressure should be reduced, and if monitoring is necessary in the absence of end-organ disease. Again, the authors caution that their recommendations are based on
limited studies.The only clear warning to emerge from the summary data for hypertensive urgencies is to avoid using oral nifedipine, which causes a rapid blood pressure reduction that is di⁄cult to titrate, and which has been associated with a TIA in two separate studies, as well as possibly worsening cardiovascular morbidity and mortality. Given the authors’own caveats on the limitation of the studies, it is somewhat surprising that they attempt to summarize the data of each study in the form of number needed to treat (NNT) and relative risk (RR) terms.The NNT term is somewhat misleading, as most clinicians would interpret it as the NNT to prevent target organ damage in the setting of treating hypertension, rather than the NNT to reduce the blood pressure. Also, the use of an RR term is confusing, as they use it to ‘give an estimate of the likelihood of the less-effective agent reaching the target BP.’ Clearly, clinicians often deal with the reality of patients with uncomfortably high blood pressure, with or without target organ damage, and the literature does not answer many clinically pertinent questions, as the authors list in their discussion: K
K K
K K
What medication is optimal for di¡erent hypertensive emergencies? What blood pressure level def|nes a hypertensive urgency? How quickly blood pressure should be decreased in a hypertensive urgency/emergency? When should maintenance therapy be started? Should patients with hypertensive urgencies be treated in observed settings?
After seeing the entirety of the literature on hypertensive emergencies and urgencies, it is apparent that past studies are not adequate to answer these questions. Clinicians must make decisions based on judgment and current practice, which advises a 25% reduction of the mean arterial blood pressure within 2 hours, or to 160/100 within 6 hours for hypertensive emergencies. Medication choices are often determined by the specific organ system involved.There is no clear timeline for the treatment of urgent hypertension, and clinical practice ranges from blood pressure reduction over hours to days.6 The Cherney review serves the medical community by demonstrating the paucity of the literature and highlighting the questions that remain. The authors may go too far in trying to extrapolate the data from extremely small studies into clinically useful parameters, but in the end, I agree with their final comments, in hoping that high-quality studies will address the questions about hypertensive urgencies and emergencies in the future. Anna P.Quan MD Assistant Clinical Professor of Medicine San Diego VA Medical Center University of California, San Diego
Literature cited 1. Chobanian AV, Bakris GL, Black HR,Cushman WC,Green LA, Izzo Jr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC VII Report. JAMA 2003; 289: 2560 ^2571. 2. Cherney D, Straus S. Management of patients with hypertensive urgencies and emergencies. J Gen Intern Med 2002; 17: 937^945. Evidence-based Cardiovascular Medicine (2003) 7,150 ^152
151
3. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 2413^2445. 4. Murphy MB, Murray C, Shorten GD. Drug therapy: fenoldopam ^ a selective peripheral dopamine-receptor agonist for the treatment of severe hypertension. N Engl J Med 2001; 345: 1548 ^1557.
152
Evidence-based Cardiovascular Medicine (2003) 7,150 ^152
5. Varon J, Marik PE., The diagnosis and management of hypertensive crises. Chest 2000; 118: 214 ^227. 6. Elliott WJ. Hypertensive emergencies.Crit Care Clin. 2001; 17: 435^ 451.
Insufficient reliable evidence about treating hypertensive emergencies Abstracted from: Cherney D, Straus S. Management of patients with hypertensive urgencies and emergencies. A systematic review of the literature. J Gen Intern Med 2002; 17: 937^945.
BACKGROUND Many antihypertensive medications exist but there is little evidence on their relative e¡ectiveness in hypertensive emergencies (where endorgan damage has occurred) or urgencies (where there is an increased risk of short-term morbidity, but not end-organ damage). OBJECTIVE To assess the evidence for the relative e¡ectiveness of di¡erent antihypertensive regimens in reducing blood pressure to safe levels in hypertensive emergencies or urgencies. METHOD Systematic review. SEARCH STRATEGY MEDLINE, reference lists and the Cochrane Library were searched. Search date 2001. INCLUSION/EXCLUSION CRITERIA Randomised controlled trials; cohort studies; systematic reviews including studies with these designs; all-ornone studies (all patients died before the medication under test was available but now some survive using it, or, some died before but now none die), and outcomes research (description of e¡ectiveness in practice rather than in a trial situation). No language restrictions. Adults with hypertensive urgencies or emergencies. DATA ANALYSIS Narrative synthesis. Where available, number needed to treat (NNT) was calculated using the Mount Sinai Hospital Center for Evidence Based Medicine Statistics Calculator. MAIN OUTCOMES T|me required for drug to reduce blood pressure to target levels. MAIN RESULTS Hypertensive emergencies: One randomised controlled trial was identi¢ed, which found no signi¢cant di¡erence between captopril and nifedipine for reducing diastolic blood pressure below 120 mmHg and eliminating symptoms at 60 minutes (NNT for captopril v nifedipine 5, 95% CI; NNH 2 to NNT 5).Three other, poorer quality studies found that nifedipine
150
Evidence-based Cardiovascular Medicine (2003) 7,150 ^152 doi:10.1016/S1361-2611(03)00062-9
reduced blood pressure to target levels more quickly than nitroprusside (4.5 v 14.2 hours, po0.05), and found that urapidil was better than nitroprusside in reducing blood pressure to target levels within 90 minutes (NNT 12; 95% CI 5 to+40). Hypertensive urgencies: Fifteen studies were identi¢ed, 10 of which were randomised controlled trials. Findings were as follows: K
K
K
K
K
K
K
Nicardipine lowered blood pressure to target levels in more patients than placebo (65% v 22%, p = 0.002, NNT 2). Long-acting lacidipine was more e¡ective at controlling the blood pressure at 24 hours than nifedipine ( p = 0.001, NNT 2). Control of blood pressure was greater with urapidil than nifedipine after a single dose (92% v 70%, po0.04, NNT 5). Control of blood pressure was greater with nifedipine than clonidine (NNT 2). Enalaprilat was not signi¢cantly more e¡ective than placebo in people with moderate hypertension (diastolic blood pressure 100 to 144 mmHg) and was not signi¢cantly more e¡ective than furosemide in people with severe hypertension (diastolic blood pressure 115 to 130). Oral nifedipine was of similar e⁄cacy to oral labetolol or nitrendipine ( p40.05). Fenoldopam was of similar e⁄cacy to nitroprusside ( p40.05).
AUTHORS’ CONCLUSIONS Evidence about e¡ectiveness of antihypertensive agents in people with hypertensive emergencies or hypertensive urgencies is weak. Studies had small sample sizes and were heterogeneous in terms of patients, interventions and outcomes reported. Limited evidence suggests that urapidil is most e¡ective in emergencies. In urgencies, nicardipine; lacidipine; urapidil; nitroprusside or fenolodopam may be used, but not nifedipine. Sources offunding: Notspeci¢ed. Correspondence to: D Cherney, 50 Walmer Road, Apt107,Toronto, Ontario, M5R 2X4. Email: [email protected] Abstract provided by Bazian Ltd, London.
1361-2611/03/$ - see front matter & 2003 Elsevier Ltd. Allrights reserved.
Commentary Hypertensive emergencies and urgencies affect approximately 1% of all hypertensive patients. However, according to the recently published JNC VII guidelines for hypertension, there are more than 50 million hypertensive patients in the United States and up to 1 billion worldwide.1 Thus, hypertensive urgencies and emergencies are a common problem in the emergency room ^ up to 3% of all emergency visits. Unfortunately, there are few high-quality studies that address the problem of hypertensive emergencies and urgencies, and so most of the clinical management of hypertensive crises is based on clinical judgment rather than on evidence-based literature. The Cherney review2 has carefully assembled many of the better studies on hypertensive emergencies and urgencies from 1966 to 2001, but then attempts to clarify treatment options based on small studies with di¡erent inclusion criteria, treatments, and outcomes. The authors recognize the disparities between studies and appropriately include warnings throughout their review that the purpose of their study is ‘to show what is known and what is not known, about hypertensive urgencies and emergencies.’ Part of the problem of summarizing studies on hypertensive emergencies and urgencies is the lack of clear definitions. A hypertensive emergency is defined by JNC VI as a ‘rare situation that requires immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage,’ with the most common organ systems involved being the central nervous system, cardiovascular, pulmonary, renal, ophthalmologic, or the fetus in pregnancy.3 InTable 2 of the Cherney review, only four studies are categorized under hypertensive emergencies, and their inclusion criteria are markedly different, ranging from patients with evidence of end-organ damage, such as eye ground changes, to patients recruited with severe high blood pressure, with no explicit exclusion of end-organ damage. The authors themselves seem a bit discomfited by their concluding statement that urapidil has the most effective number needed to treat, since it was only used in a single study, and the result is not statistically significant. Also, the studies included do not address the more severe hypertensive emergencies, in which treatment is often driven by the specific end-organ affected. For instance, in the setting of an acute myocardial infarction with greatly elevated blood pressure, intravenous nitroglycerin might be preferred, whereas in the setting of an aortic dissection, a beta-blocker should be used before a nitrate is added in order to minimize wall stress. Fenoldapam, a dopamine-1 receptor agonist, might be preferred in the setting of worsening renal insufficiency in order to increase renal vasodilatation.4 In the setting of an acute stroke, clinicians should avoid rapid blood pressure reduction since cerebral damage can be worsened by ischemia.5 The definition of ‘hypertensive urgencies’ is most often described as severely elevated blood pressure with no evidence of target organ damage. However, there is no consensus on the threshold for ‘severe’ blood pressure elevation. The lack of consensus is seen inTable 3 of the review, where the included studies used different BP criteria, including a diastolic blood pressure (DBP) of110 ^140, DBP 4120, DBP116 ^139, or systolic blood pressure (SBP) 4 200 and/or DBP 4 110.The lack of a clear def|nition for urgent hypertension makes it a di⁄cult problem to treat. Since most of the patients presenting with severely elevated blood pressure have chronic essential hypertension, it is unclear how quickly their blood pressure should be reduced, and if monitoring is necessary in the absence of end-organ disease. Again, the authors caution that their recommendations are based on
limited studies.The only clear warning to emerge from the summary data for hypertensive urgencies is to avoid using oral nifedipine, which causes a rapid blood pressure reduction that is di⁄cult to titrate, and which has been associated with a TIA in two separate studies, as well as possibly worsening cardiovascular morbidity and mortality. Given the authors’own caveats on the limitation of the studies, it is somewhat surprising that they attempt to summarize the data of each study in the form of number needed to treat (NNT) and relative risk (RR) terms.The NNT term is somewhat misleading, as most clinicians would interpret it as the NNT to prevent target organ damage in the setting of treating hypertension, rather than the NNT to reduce the blood pressure. Also, the use of an RR term is confusing, as they use it to ‘give an estimate of the likelihood of the less-effective agent reaching the target BP.’ Clearly, clinicians often deal with the reality of patients with uncomfortably high blood pressure, with or without target organ damage, and the literature does not answer many clinically pertinent questions, as the authors list in their discussion: K
K K
K K
What medication is optimal for di¡erent hypertensive emergencies? What blood pressure level def|nes a hypertensive urgency? How quickly blood pressure should be decreased in a hypertensive urgency/emergency? When should maintenance therapy be started? Should patients with hypertensive urgencies be treated in observed settings?
After seeing the entirety of the literature on hypertensive emergencies and urgencies, it is apparent that past studies are not adequate to answer these questions. Clinicians must make decisions based on judgment and current practice, which advises a 25% reduction of the mean arterial blood pressure within 2 hours, or to 160/100 within 6 hours for hypertensive emergencies. Medication choices are often determined by the specific organ system involved.There is no clear timeline for the treatment of urgent hypertension, and clinical practice ranges from blood pressure reduction over hours to days.6 The Cherney review serves the medical community by demonstrating the paucity of the literature and highlighting the questions that remain. The authors may go too far in trying to extrapolate the data from extremely small studies into clinically useful parameters, but in the end, I agree with their final comments, in hoping that high-quality studies will address the questions about hypertensive urgencies and emergencies in the future. Anna P.Quan MD Assistant Clinical Professor of Medicine San Diego VA Medical Center University of California, San Diego
Literature cited 1. Chobanian AV, Bakris GL, Black HR,Cushman WC,Green LA, Izzo Jr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC VII Report. JAMA 2003; 289: 2560 ^2571. 2. Cherney D, Straus S. Management of patients with hypertensive urgencies and emergencies. J Gen Intern Med 2002; 17: 937^945. Evidence-based Cardiovascular Medicine (2003) 7,150 ^152
151
3. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 2413^2445. 4. Murphy MB, Murray C, Shorten GD. Drug therapy: fenoldopam ^ a selective peripheral dopamine-receptor agonist for the treatment of severe hypertension. N Engl J Med 2001; 345: 1548 ^1557.
152
Evidence-based Cardiovascular Medicine (2003) 7,150 ^152
5. Varon J, Marik PE., The diagnosis and management of hypertensive crises. Chest 2000; 118: 214 ^227. 6. Elliott WJ. Hypertensive emergencies.Crit Care Clin. 2001; 17: 435^ 451.