ORIGINAL ARTICLE
Year : 2017 | Volume
: 14 | Issue : 1 | Page : 19--25
Hypertension treatment by primary care physicians in Lagos
Olagoke Korede Ale1, Rotimi William Braimoh2,
1 Cardiology, Department of Medicine, College of Medicine, University of Lagos/Lagos University Teaching Hospital, Lagos, Nigeria
2 Nephrology Units, Department of Medicine, College of Medicine, University of Lagos/Lagos University Teaching Hospital, Lagos, Nigeria
Correspondence Address:
Olagoke Korede Ale
Cardiology Unit, Department of Medicine, College of Medicine, University of Lagos/Lagos University Teaching Hospital, PMB 12003, Lagos
Nigeria
Abstract
Background: Globally, hypertension (HTN) control is poor. We studied the contribution of primary care physicians to this.
Methods: Lagos-based primary care physicians were studied using anonymous self-administered questionnaire on HTN treatment goals and drug therapy.
Results: Data from 403 respondents with a mean age and experience of 40 ± 11.34 years and 14.3 ± 11.1 years, respectively, were analyzed. Two hundred and twenty-eight physicians (61.1%) practiced in primary health-care facilities, while 125 (33.5%) and 20 (5.4%) practiced in facilities affiliated to the secondary and tertiary health-care centers, respectively. One hundred and twenty-three (35.7%) of the respondents correctly indicated the treatment blood pressure goal for uncomplicated HTN. Eighty (26.1%), 37 (12.2%), and 54 (18.5%) of respondents correctly indicated the treatment goals in hypertensive patients with diabetes mellitus (DM), old stroke, and coronary artery disease (CAD), respectively. The correct choice(s) of antihypertensive drugs vis-a-vis compelling/possible indications were made by 259 (76%) for uncomplicated HTN, 194 (63.4%) for hypertensives with chronic kidney disease, 128 (44.3%) for hypertensives with previous stroke, 250 (76.7%) for pregnant hypertensives, 166 (57%) for hypertensives with CAD, and 165 (61.6%) for hypertensives with DM. Choice(s) of antihypertensive medications were determined by the patient's age 302 (79.4%), gender 233 (58.4%), race 234 (59.8%), associated clinical condition 365 (90.6%), duration of action of antihypertensive drugs 340 (85.5%), and the cost of antihypertensive medications: 334 (85%).
Conclusions: The physicians' knowledge of HTN management is suboptimal. This may be contributory to the poor HTN control in Nigeria. These deficiencies may be addressed through continuing medical education together with popularizing and simplifying of the guidelines.
How to cite this article:
Ale OK, Braimoh RW. Hypertension treatment by primary care physicians in Lagos.Nig J Cardiol 2017;14:19-25
|
How to cite this URL:
Ale OK, Braimoh RW. Hypertension treatment by primary care physicians in Lagos. Nig J Cardiol [serial online] 2017 [cited 2023 Apr 2 ];14:19-25
Available from: https://www.nigjcardiol.org/text.asp?2017/14/1/19/201903 |
Full Text
Introduction
The management of hypertension (HTN) has been one of medicine's major successes of the past five decades.[1] Despite the remarkable advances in the management of HTN, it continues to be a major public health problem worldwide with an increasing prevalence.[1] HTN is the biggest single contributor to the global burden of disease and mortality.[2] The estimated global prevalence of HTN in adults aged 25 and over was 40% in 2008.[3] Across the WHO regions, Africa has the highest HTN prevalence of 46% with Nigeria having an estimated overall HTN prevalence of 28.9%.[3],[4]
Globally, HTN is characterized by increasing prevalence, suboptimal evaluation, and poor blood pressure (BP) control.[1],[4],[5],[6] This is particularly more applicable to developing countries such as Nigeria.[5],[6] According to Kearney et al.,[7] about 75% of the global hypertensive population will be residing in developing countries such as Nigeria by 2025. In Nigeria, HTN is the number one risk factor for stroke, heart failure, ischemic heart disease, and kidney failure.[6]
A combination of health-care system, health professional, and patient factors in varying degrees have been implicated in poor HTN control.[8] Limited knowledge of health-care professionals about HTN has been documented as a major reason for poor diagnosis and management of HTN in various parts of the world.[9],[10],[11] This includes physicians, whose inability to provide good management of HTN has been identified as an important contributor to poor BP control in hypertensive patients.[12]
HTN is not just the most common condition managed in primary care but is also mostly managed by primary care physicians.[13],[14] The primary health-care facility is also the first point of call for over 55% of the Nigerian population.[15] About half of Nigerians live in urban settlements.[15] Assessment of the treatment of HTN by urban-based primary care physicians may yield findings that may inform new strategies for HTN control in Nigeria. We have previously documented the approach of this cohort of primary care physicians to the diagnosis and evaluation of HTN.[5] The current study sought to evaluate the knowledge of HTN treatment by this cohort of primary care physicians based in Lagos.
Methods
Four hundred and three Lagos-based primary care physicians (general practitioners) attending continuing medical education programs were studied using anonymous self-administered questionnaire consisting of open- and closed-ended questions on the HTN treatment. The closed-ended questions had either yes/no or Likert-type scale responses. The study questionnaire was in three main themes: (1) treatment goals for HTN-open ended, (2) drug therapy in HTN: (2a) first line therapy for HTN-closed ended and (2b) compelling/possible indications for antihypertensive drugs– open ended, and (3) factors influencing the choice of antihypertensive medications – Likert-type scale. A yes/no question on the awareness of guidelines on HTN was included in the study.
Ethical clearance was obtained from the Ethics and Research Committee of the Lagos University Teaching Hospital. Consent of each participant was obtained.
Statistical analysis
Outcome variables
Likert-type scale responses were transformed into dichotomous responses of correct/yes (”always done” and “often or usually done”) and incorrect/no (”sometimes done,” “occasionally done,” and “rarely or never done”) responses.
Systolic and/or diastolic BP values higher than the correct BP target were taken as being higher than the target BP. BP values were taken as being lower than correct BP target if (i) both systolic and diastolic BP were lower than correct target or (ii) systolic BP was less than correct target with diastolic BP on target or (iii) systolic BP was on target while the diastolic BP was less than correct BP target. BP values were taken as being higher than correct BP target if (i) both systolic and diastolic BP were higher than correct target and (ii) systolic BP was higher than correct target with diastolic BP on target or (iii) systolic BP was on target while the diastolic BP was higher than correct BP target.
The outcomes were defined based on the International Forum for HTN control and prevention in Africa (IFHA) recommendations for prevention diagnosis and management of HTN and cardiovascular (CV) risk factors in sub-Saharan Africa.[16]
Statistics
All the statistical data were analyzed using the SPSS for windows version 20 (Armonk, NY, USA). Descriptive statistics were used to report the findings. Categorical variables were expressed as proportions while continuous variables were expressed as mean ± standard deviation; statistical significance of variables was tested using Chi-square for categorical variables. All tests were two-tailed and values were considered statistically significant if P < 0.05.
Results
Data from 403 physicians with a mean age of 40 ± 11.34 years and age range of 26–72 years were analyzed. The cohort consisted of 249 (61.8%) males and 154 (38.2%) females. The physicians had a mean postregistration experience of 14.30 ± 11.10 years which ranged from 1 to 38 years. Two hundred and sixty-nine (66.7%) and 134 (33.3%) of the respondents were in private and public practice, respectively. These physicians attended to 17.39 ± 14.25 patients/day. [Figure 1] shows the age distribution of the respondents.{Figure 1}
Two hundred and twenty-eight physicians (61.1%) practiced in primary health-care facilities, while 125 (33.5%) and 20 (5.4%) practiced in facilities affiliated to secondary and tertiary health-care centers, respectively. One hundred and eighty-eight (46.7%) physicians responded affirmatively to awareness of HTN guidelines, while 215 (53.3%) physicians were unaware of HTN guidelines.
For patients with uncomplicated HTN, 123 (35.7%) respondents correctly indicated the treatment BP goal, while the remaining respondents, i.e., 208 (60.3%) and 14 (4.1%) aimed for BP values lower and higher, respectively, than the correct treatment goal. BP goal for patients with diabetes mellitus (DM) was correctly indicated by eighty (26.1%) physicians, while the remaining 94 (27.9%) and 155 (46%) respondents indicated BP values lower and higher, respectively, than this target BP. The correct target BP for hypertensive patients with old stroke was aimed for by 37 (12.2%) respondents, while 65 (21.4%) and 202 (66.4%) aimed for BP values lower and higher, respectively, than the target BP. Fifty-four (18.5%) physicians indicated correct BP goal for hypertensive patients with coronary artery disease (CAD), while 96 (32.9%) and 142 (48.6%) aimed for values lower and higher, respectively, than this BP target. The correct treatment goal for hypertensives aged ≥ 60 years was indicated by 158 (47.2%) respondents, while 93 (27.3%) and 84 (25.1%) aimed for BP values lower and higher, respectively, than this treatment goal.
[Table 1] shows the respondents with correct BP target(s) for HTN according to their experience, type of practice, and HTN guidelines awareness.{Table 1}
Antihypertensive drug(s) alone were chosen by 116 (23.9%) physicians as the first line therapy for BP lowering. Sedatives alone and a combination of sedatives and antihypertensive drug(s) were chosen as the first line therapy for BP lowering by 187 (47%) and 95 (23.9%) physicians, respectively. [Table 2] shows the physicians' first choice therapy for BP lowering according to experience, type of practice, and HTN guidelines awareness of the respondents.{Table 2}
The correct choice(s) of antihypertensive drugs vis-a-vis compelling and possible indications were made by the physicians in the following conditions; 259 (76%) for uncomplicated HTN, 194 (63.4%) for hypertensives with chronic kidney disease (CKD), 128 (44.3%) for hypertensives with previous stroke, 250 (76.7%) for pregnant hypertensives, 166 (57%) for hypertensives with CAD, and 165 (61.6%) for hypertensives with DM. [Table 3] shows the physicians with the correct choice of antihypertensive drugs vis-a-vis compelling and possible indications.{Table 3}
Factors which determined the choice of antihypertensive medications by this cohort are patient's age: 302 (79.4%), gender of the patient: 233 (58.4%), race of the patient: 234 (59.8%), associated clinical condition of patients: 365 (90.6%), duration of action of antihypertensive drugs: 340 (85.5%), and the cost of antihypertensive medications: 334 (85%).
Only ten (2.5%) physicians discontinued antihypertensive medications on the attainment of BP control while the remaining 388 (97.5%) continued therapy.
Discussion
Untreated and poorly treated HTN is associated with increased risk of CV morbidity and mortality.[1],[5] However, a meta-analysis of large-scale randomized trials has shown that antihypertensive therapy produces a nearly 50% relative risk reduction in the incidence of heart failure, a 30–40% relative risk reduction in stroke, and a 20–25% relative risk reduction in myocardial infarction.[17] An observational study by Lewington et al. has shown that for individuals aged 40–70 years, each increment of 20 mmHg in systolic BP or 10 mmHg in diastolic BP doubles the risk of CV disease across the entire BP range from 115/75 to 185/115 mmHg.[18] This underscores the importance of the attainment of correct treatment BP goal in the management of HTN for the optimal achievement of the benefit of BP lowering. Most of the physicians in this study used incorrect BP target for the treatment of HTN with or without comorbidities. With the exclusion of patients with uncomplicated HTN, the general tendency for the physicians in our study was to use higher target BP values. A similar scenario where most physicians used incorrect BP targets had been reported among physicians based in Pakistan and Cameroon.[12],[19] The above may partly underlie the low BP control rate among hypertensive Nigerians.[6] This low BP control rate among hypertensive Nigerians coupled with poor HTN detection will increase the CV morbidity and mortality attributable to HTN among Nigerians. Data from medical records of 2752 hypertensive patients being managed by Slovenian primary care physicians showed that only 15.5% reached target BP values.[20] Similar data indicating poor BP control among hypertensive patients are available for the United States, Canada, and European countries.[1],[21] IFHA guidelines for sub-Saharan Africa recommended a lower BP threshold and goals for hypertensive persons with established CV disease, DM, and CKD.[16] However, the recommended BP threshold and goal by the Eighth Joint National Committee (JNC 8) for persons with HTN is independent of their CV comorbidities.[13] BP goal in HTN has thus been a moving target which may be further reduced by the time the results of a randomized trial of intensive versus standard BP control by the SPRINT research group become incorporated in HTN guidelines.[22]
The use of sedatives in the management of HTN is frequent in sub-Saharan Africa.[16] Drugs with antianxiety properties are ineffective in BP lowering and have no role in the treatment of clinical HTN.[16],[19] Over 70% of the physicians in our survey used sedatives either alone or in combination with antihypertensive drugs as initial therapy for the treatment of HTN. This practice was more common among the more experienced physicians, physicians working in the primary care centers, and facilities affiliated with the secondary care centers. This is much more than reported 45% of Pakistani physicians using sedatives in HTN treatment.[19] Inappropriate use of sedatives in the treatment of HTN may not only cause undertreatment of HTN and a consequent uncontrolled HTN but may also create a risk of drug dependence.
Most hypertensive patients require drug therapy to achieve target BP levels. There are several good agents available such as thiazide-type diuretics, beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors, calcium channel blockers, and angiotensin receptor blockers (ARBs) available for this. Several studies aimed at determining the superiority of antihypertensive drug or drug combinations have shown minimal differences in primary outcomes among the drug classes as long as the equivalent reduction in BP has been achieved.[1],[23],[24] Conversely, a few trials have shown the superiority of one drug or a given combination over another.[1],[25],[26] However, the bulk of evidence favors BP lowering regardless of how it is achieved as the most important aspect of antihypertensive therapy.[1],[13] Compelling indications for certain classes of antihypertensive drugs have been demonstrated in certain situations.[1],[16],[27] These include the use of ACE inhibitors and ARBs in patients with the chronic renal disease, diabetes, congestive heart failure, or recent myocardial infarction and beta-blockers in those with angina pectoris, recent myocardial infarction, arrhythmias, or heart failure.[1],[16],[27] Some drugs also provide added benefit when HTN coexists with other conditions (e.g., beta-blockers in a coexistent migraine headache).[1] There was a deficiency of 23–56% in the choice of drugs by this cohort vis-a-vis compelling and possible indications of antihypertensive drugs. This deficiency was most marked in cases of treatment of HTN coexisting with old stroke with only 44% of the respondents making correct choice(s). This is inconsistent with our finding in this study of over 90% of the physicians taking into account associated clinical condition when choosing antihypertensive medications. This discordance may be due to ignorance about the compelling indications of antihypertensive drugs.
IFHA guidelines recommend that low dose diuretics should be used to initiate therapy in almost all categories of patients.[16] Three-fourths of the respondents indicated the use of thiazide diuretics in the treatment of uncomplicated HTN. In addition to thiazide diuretics being the least expensive class of antihypertensive medications, there is also compelling evidence that they confer the same or even better benefit in preventing the CV complications of HTN compared to calcium channel blockers and ACE inhibitors.[27] The underprescription of thiazides denies patients of cheap and potent therapy for BP control, especially in low-income settings such as Nigeria. Underutilization of thiazide diuretics has also been documented among physicians based in Cameroon, the United States, and Pakistan.[12],[19],[28]
The major determinants of the choice of antihypertensive drugs among this cohort were patients age, cost of the drugs, and the duration of action of the drug. These are very important because of the low-income setting coupled with predominantly out of the pocket mode of paying for medical expenses which may make some drugs unaffordable. Long-acting drugs with once daily dosing also encourage adherence. However, the finding that only 58% of the cohort was mindful of the patient's gender in choosing antihypertensive drugs may be suggestive of ignorant/noncautious use of some drugs such as renin angiotensin aldosterone system blockers in women in reproductive age group. The use of this class of drugs during pregnancy has been associated with increased risk of fetopathy.[29]
The treatment of HTN is usually life-long, and discontinuation of therapy may result in preventable morbidity and mortality. It is gratifying to note that only 2.5% of the respondents stopped antihypertensive therapy on the attainment of BP target. This is comparable to 2.6% reported for physicians based in Cameroon but far better than the 25% documented for Pakistan-based physicians.[12],[19]
Physicians with ≤10 years' experience performed better than the more experienced ones in the choice of HTN treatment BP target and in the choice of antihypertensive medications. The postulated reason for this is that the more experienced physicians still base their practice on older guidelines which recommended higher target BP for patients on antihypertensive therapy. Conversely, the less experienced ones being more recent graduates of medical schools are more likely to have updated knowledge of HTN management. Our finding is however contrary to that of Cameroon and Pakistan-based physicians where the knowledge of HTN management was independent of years of experience.[12],[19]
Primary care physicians practicing in facilities affiliated to tertiary care centers expectedly performed better than those practicing in lower levels of health-care facilities. The tendency of tertiary care hospitals to have more informal and formal training of their health personnel when compared with lower levels of health-care facilities most likely explains the above findings.
The performance of physicians in government and private center with regards to choice of antihypertensive medications were similar. However, the ones in government owned health facilities were better in the choice of HTN treatment BP target. Our postulation for this finding is that government-owned facilities in addition to having more specialists in their employment are also more likely to have clinical meetings. This may have rubbed off on physicians on government owned practice resulting in their better performance.
Limitations
This survey was self-reported, hence has the likelihood of overestimating clinical behaviors/practice viewed as desirable. Data from medical records would have been ideal for determining HTN management, however making the questions on BP target and choice of compelling/possible indications for antihypertensive drugs open ended would have minimized this bias. Lagos is urban; therefore this cohort may not adequately represent the physicians practicing in rural settlements. However, since urban areas have a higher burden of HTN, commencing explorations and interventions to improve HTN control in the cities may be more impactful.[15]
Conclusions
The knowledge of HTN treatment by these physicians is inadequate. There are overt deficiencies in their knowledge of the management of HTN which may be contributory to the current inadequate HTN control in Nigeria. These deficiencies may be addressed through continuing medical education of the physicians, popularizing guidelines, and probably simplifying the guidelines.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
| 1 | Chobanian AV. Shattuck lecture. The hypertension paradox – More uncontrolled disease despite improved therapy. N Engl J Med 2009;361:878-87. |
| 2 | Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet 2015;386:801-12. |
| 3 | Available from: http://www.who.int/gho/ncd/risk_factors/blood_pressure_prevalence_text/en/. [Last accessed on 2015 Nov 02]. |
| 4 | Adeloye D, Basquill C, Aderemi AV, Thompson JY, Obi FA. An estimate of the prevalence of hypertension in Nigeria: A systematic review and meta-analysis. J Hypertens 2015;33:230-42. |
| 5 | Ale OK, Braimoh RW, Olayemi SO. The approach of general practitioners in Lagos to the detection and evaluation of hypertension. Clin Hypertens 2015;21:10. |
| 6 | Ogah OS, Okpechi I, Chukwuonye II, Akinyemi JO, Onwubere BJ, Falase AO, et al. Blood pressure, prevalence of hypertension and hypertension related complications in Nigerian Africans: A review. World J Cardiol 2012;4:327-40. |
| 7 | Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: Analysis of worldwide data. Lancet 2005;365:217-23. |
| 8 | Fahey T, Schroeder K, Ebrahim S. Educational and organisational interventions used to improve the management of hypertension in primary care: A systematic review. Br J Gen Pract 2005;55:875-82. |
| 9 | Mungati M, Manangazira P, Takundwa L, Gombe NT, Rusakaniko S, Tshimanga M. Factors affecting diagnosis and management of hypertension in Mazowe District of Mashonaland Central Province in Zimbabwe: 2012. BMC Cardiovasc Disord 2014;14:102. |
| 10 | Zibaeenezhad MJ, Babaee H, Vakili SH. Knowledge, attitude and practice of general physicians in treatment and complications of hypertension in Fars province, Southern Iran. Iran Red Crescent Med J 2007;9:4-8. |
| 11 | Rehman A, Rehman T, Shaikh MA, Naqvi SA. Awareness of hypertension among the medical students and junior doctors – A multicenter study from Pakistan. J Pak Med Assoc 2011;61:1153-7. |
| 12 | Noubiap JJ, Jingi AM, Veigne SW, Onana AE, Yonta EW, Kingue S. Approach to hypertension among primary care physicians in the West Region of Cameroon: Substantial room for improvement. Cardiovasc Diagn Ther 2014;4:357-64. |
| 13 | James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507-20. |
| 14 | Frijling BD, Spies TH, Lobo CM, Hulscher ME, van Drenth BB, Braspenning JC, et al. Blood pressure control in treated hypertensive patients: Clinical performance of general practitioners. Br J Gen Pract 2001;51:9-14. |
| 15 | Akinlua JT, Meakin R, Umar AM, Freemantle N. Current prevalence pattern of hypertension in Nigeria: A systematic review. PLoS One 2015;10:e0140021. |
| 16 | Lemogoum D, Seedat YK, Mabadeje AF, Mendis S, Bovet P, Onwubere B, et al. Recommendations for prevention, diagnosis and management of hypertension and cardiovascular risk factors in sub-Saharan Africa. J Hypertens 2003;21:1993-2000. |
| 17 | Blood Pressure Lowering Treatment Trialists' Collaboration, Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: Meta-analysis of randomised trials. BMJ 2008;336:1121-3. |
| 18 | Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-13. |
| 19 | Jafar TH, Jessani S, Jafary FH, Ishaq M, Orakzai R, Orakzai S, et al. General practitioners' approach to hypertension in urban Pakistan: Disturbing trends in practice. Circulation 2005;111:1278-83. |
| 20 | Petek-Ster M, Kersnik J, Svab I. Compliance with hypertension guidelines in general practice in Slovenia. Srp Arh Celok Lek 2007;135:191-6. |
| 21 | Wolf-Maier K, Cooper RS, Kramer H, Banegas JR, Giampaoli S, Joffres MR, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension 2004;43:10-7. |
| 22 | SPRINT Research Group, Wright JT Jr., Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A Randomized trial of intensive versus Standard blood-pressure control. N Engl J Med 2015;373:2103-16. |
| 23 | ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97. Erratum in: JAMA 2003;289:178, 2004;291:2196. |
| 24 | Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 2003;290:2805-16. |
| 25 | Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, et al. A comparison of outcomes with angiotensin-converting – Enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583-92. |
| 26 | Jamerson K, Weber M, Bakris G, Dahlöf B, Pitt B, Shi V, et al. ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-28. |
| 27 | Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr., et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA 2003;289:2560-72. Erratum in: JAMA 2003;290:197. |
| 28 | Psaty BM, Manolio TA, Smith NL, Heckbert SR, Gottdiener JS, Burke GL, et al. Time trends in high blood pressure control and the use of antihypertensive medications in older adults: The Cardiovascular Health Study. Arch Intern Med 2002;162:2325-32. |
| 29 | Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006;354:2443-51. |
|
