Abstract
Background. Recent guidelines recommended different approaches to hypertension therapy. Our aim was to evaluate trends in blood pressure (BP) management among patients admitted with acute stroke over the past decade. Methods. The study population comprised 6279 consecutive patients, admitted with an acute stroke, and included in a national registry of three consecutive periods conducted during the years 2004–2010. We compared patients’ characteristics and temporal trends of antihypertensive therapy utilization before hospital admission. Results. Among 4727 hypertensive patients, 3940 (83%) patients have taken antihypertensive drug therapy – 1430 (30.2%) a single agent, 1500 (31.7%) two agents and 1010 (21.4%) three or more antihypertensive agents. The most common class used was renin–angiotensin system (RAS) blockers (n = 2575; 54%) followed by beta-blockers (n = 2033; 43%). The same pattern was observed in patients treated with monotherapy. The use of RAS blockers and beta-blockers has increased over the years (p < 0.001 for both), whereas the use of diuretics decreased and the use of calcium antagonists remained stable. Among those who were treated with a single agent, the use of diuretics and calcium antagonists decreased and the use of RAS blockers increased, whereas the use of beta-blockers remained unchanged. Conclusions. RAS blockers and beta-blockers are the most common antihypertensive agents used in Israel. Over time, the use of RAS blockers and beta-blockers has increased, whereas the use of diuretics decreased.
Introduction
Hypertension is a significant treatable cause of cardiovascular (CV) morbidity and mortality (Citation1,Citation2), which lays an enormous burden on public health (Citation3). Evidence shows that reduction in blood pressure (BP) in hypertensive patients results in a significant reduction in the incidence of CV events, end organ damage and subsequent mortality (Citation4). Current guidelines recommend a combined approach for treatment of hypertensive patients, which consists of lifestyle modifications (Citation5,Citation6) and pharmacologic therapy (Citation7–10).
The management of hypertension has been extensively studied in recent years, leading to a rise in awareness and treatment in various patient groups. Yet, despite the vast research in the field, according to recent publications 30–50% of hypertensive patients still have uncontrolled hypertension (Citation11,Citation12).
Of the many drugs used to treat hypertension, four groups are considered the mainstay therapy in most patients: angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB), which block the renin–angiotensin system (RAS), and are considered equivalent (Citation13); calcium antagonists; diuretics, especially the thiazide group; and beta-blockers, which are considered less effective (Citation14,Citation15) and were recently not recommended by the British National Institute for Health and Care Excellence (NICE) as mono-therapy for hypertension (Citation8).
Using the National Acute Stroke Israeli (NASIS) registry of three consecutive periods conducted during the years 2004–2010, we sought to determine the temporal trends in antihypertensive drug therapy in light of the guidelines of major societies (Citation7–10,Citation16).
Methods
The NASIS is a nationwide hospital-based registry conducted triennially during 2-month periods since 2004. All adult patients with acute cerebrovascular disease admitted to any of the 28 hospitals nationwide during February–March 2004 (NASIS 2004), March–April 2007 (NASIS 2007) and March–April 2010 (NASIS 2010) were included. All NASIS study periods used similar methods and data retrieval sheets to collect pertinent demographic, clinical, radiological and outcome measures, as previously detailed (Citation17).
In this report, we focus on hypertensive patients admitted with stroke and included in the NASIS registry. Medical history and therapy before admission were derived based on admission and discharge records. Hypertensive patients were identified according to a history of or diagnosis of hypertension (> 140/90 mmHg) before the index stroke/transient ischemic attack (TIA) with or without medical treatment. Diabetes mellitus (DM) was defined as fasting glucose above 126 mg/dl (7 mmol/l) prior to the index event or a history of diabetes requiring diet or oral hypoglycemic medications or insulin. Ischemic heart disease (IHD) was identified according to documentation of active or prior angina pectoris, or prior diagnosis of myocardial infarction (MI) (including silent MI). Congestive heart failure (CHF) was defined by prior diagnosis of CHF, or signs and symptoms indicative of CHF, or ejection fraction < 30%. Prior stroke was defined per medical history.
Statistical analysis
We divided hypertensive patients enrolled in NASIS to four groups according to hypertensive drug treatment, consisting of beta-blockers, calcium antagonists, diuretics, and ACE-I or ARB. Thus patients treated with more than one drug were included in more than one group. Further adjustments were made for age, gender and medical conditions influencing therapy, such as DM, IHD, CHF and creatinine level.
Subgroup analysis was conducted in order to assess the influence of different variables on drug choice such as gender, age, DM, past stroke or TIA, CHF and IHD. A similar analysis was done in hypertensive patients with a single-class drug therapy as a representative of first-line treatment in order to observe the changing trends in recent years in the various sub-groups.
Results
Patients’ characteristics
Among 6279 patients who were admitted with acute cerebrovascular disease (stroke or TIA) during the registry periods, 4761 (75%) had a history of hypertension. The rate of recorded hypertension has slightly increased over the years from 75% in 2004, to 76% in 2007 and 78% in 2010 (p = 0.008). The rate of patients with peripheral artery disease and prior disability decreased, and the rate of patients with dyslipidemia, smoking and malignancy increased ().
Table I. Baseline characteristics of hypertensive patients in the National Acute Stroke Israeli registry.
Antihypertensive treatment
Among 4727 hypertensive patients with records on antihypertensive treatment, 3940 (83%) patients have taken antihypertensive drug therapy; 1430 (30%) were treated with a single agent, 1500 (32%) with two agents and 1010 (21%) with three or more antihypertensive agents.
The most common class used, throughout the study period was RAS blockers (ACE-I or ARB), used by 2575 (54%) of the hypertensive patients. The next most common class was beta-blockers used by 2033 (43%) patients. Calcium antagonists were taken by 1536 (32%) patients and diuretics were used by 1483 (31%) patients.
Antihypertensive drug therapy increased with age for diuretics, calcium antagonists and beta-blockers, but tended to decrease for RAS blockers (). Women were more likely than men to be treated with diuretics, calcium antagonists and beta-blockers (). Patients with CHF were more likely to be treated with beta-blockers, RAS blockers and diuretics, but not with calcium antagonists (). Patients with IHD, DM and with a history of stroke were more likely to be treated with any of the antihypertensive agents, this was also seen in diabetic patients ().
Figure 1. Use of antihypertensive therapy by age in the entire hypertensive population (A) and in patients on monotherapy (B). *p = 0.003, †p < 0.001, ‡p = 0.08.
Figure 2. Antihypertensive therapy distribution by gender in the entire hypertensive population (A) and in patients on monotherapy (B). *p < 0.001, †p = 0.02, ‡p = 0.078.
Table II. Antihypertensive therapy according to concomitant diseases in the entire cohort and among patients on monotherapy.
Monotherapy in hypertensive patients
Among 1430 hypertensive patients treated with monotherapy, the most common drug class was RAS blockers, used by 652 (46%) patients, followed by beta-blockers used by 389 (27%) patients, calcium antagonists used by 273 (19%) patients and diuretics by 116 (8%) patients.
Temporal trends by drug classes revealed that the use of calcium antagonists and diuretics increased, whereas the use of RAS blockers decreased with age (). Gender analysis revealed that calcium antagonists were more commonly used among women while RAS blockers had a trend to be more commonly used among men (). Patients with IHD were more likely to be treated with beta-blockers and diuretics, and less likely to be treated with RAS blockers than those without IHD (). Patients with DM were more likely to be treated with RAS blockers and less likely to be treated with beta-blockers and diuretics than non-diabetic patients ().
Trends of antihypertensive treatment between periods
The use of diuretics decreased significantly and was pronounced in 2010 compared with 2007. The use of beta-blockers and RAS blockers increased between 2004 and 2007, a trend that was attenuated in 2010, but still represents an increase in utilization of these drug classes. The use of calcium antagonists remained unchanged.
Among those who were treated with a single agent, the use of diuretics and calcium antagonists decreased mainly between 2010 and 2007. The use of RAS blockers increased whereas the use of beta-blockers remained unchanged (). The rate of monotherapy remained the same, whereas the rate of using combination of three and more agents increased ().
Figure 3. Trend of antihypertensive drugs used over the years in patients on monotherapy. *p = 0.01, †p = 0.004, ‡p = 0.03 vs 2004.
Figure 4. Trends in quantity of antihypertensive agents used over the years. *p = 0.04 vs 2004.
Further analysis of the trends of antihypertensive use throughout the years in the entire hypertensive cohort and in those who were treated with monotherapy demonstrates that age, gender, concomitant diseases and renal function did not influence trends in antihypertensive therapy ().
Table III. Odds ratios for antihypertensive drug therapy according to period.
Discussion
Findings from the NASIS registry demonstrate the popularity of ACE-I/ARB and beta-blockers in comparison to calcium antagonists and diuretics. While large-scale meta-analysis suggest that the benefit of achieving target BP is more important than the specific therapy, which enabled lowering BP values (Citation18,Citation19), some evidence shows that specific drug classes are superior to others in specific patient groups.
RAS blockers were the most common class used and their use increased. The evidence for benefit of ACE-I/ARB derives mainly from studies in high-risk patients such as CHF and diabetic nephropathy patients (Citation20–22), while evidence for superiority of RAS blockers over other antihypertensive agents in other hypertensive patient populations is limited (Citation18). A randomized, double-blind multi-center trial showed superior response in term of BP reduction in young patients (Citation23) leading to preference of RAS blockers in young hypertensive patients according to the NICE guidelines. However, most societies have no preference for one agent over the other as first-line therapy in otherwise healthy patients (Citation9,Citation10). RAS blockers were also the most common antihypertensive therapy in diabetic patients, as recommended by current guidelines (Citation7–10,Citation24,Citation25). The increased use of RAS blockers was significant even after adjustment for concomitant diseases, thus the increase cannot be attributed solely to comorbidities.
Beta-blockers, which have detrimental metabolic effects and are the least potent class of all, were the second most common class in our survey with an increased utilization after 2004. About a third of the patients in our survey had IHD and about 14% had CHF – two conditions that justify using beta-blockers. In addition, more than 20% of the patients required triple or more antihypertensive agents and this increased. Beta-blockers were also the second most common single agent; however, their utilization rate as a single agent remained unchanged.
Several studies have shown the effectiveness of thiazide diuretics as antihypertensive agents (Citation26–32). This effect was especially pronounced in the elderly and previous stroke patients (Citation33–35). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) has demonstrated the thiazide superiority over calcium antagonists and ACE-I in heart failure prevention, without any difference between pre-specified subgroups, including diabetics. This superior effect was shown even after adjustment for BP values (Citation36). Based on these data, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended thiazide as the preferred initial drug for hypertension (Citation7). However, the Australian National Blood Pressure Study (ANBP)-2 (Citation30) has shown in an open-labeled design that ACE-I are superior to thiazide. Thiazide diuretics were also found inferior to calcium antagonists when added to an ACE-I regimen in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) (Citation37).
Hydrochlorothiazide, which is the most popular thiazide in Israel, is less potent and has a shorter half time than chlorthalidone, which was used in most hypertension trials (Citation38), and its usual doses are less effective in BP reduction (Citation39) and cardiovascular outcome prevention (Citation40). The decline in thiazide use could be at least partly attributed to the adverse effects profile, which includes elevated triglycerides and glucose levels and reduced high-density lipoprotein cholesterol (Citation41–43), together with hyponatremia, which is a common side-effect, particularly in elderly women (Citation44), who comprise a large proportion of hypertensive population. Indeed the recent NICE guidelines downgraded thiazide diuretics to the third place after RAS blockers and calcium antagonists (Citation8). Despite the decrease use of diuretics, its use increased with age and it was commonly used in patients with CHF.
We also noted that calcium antagonists were used less commonly than RAS blockers and beta-blockers, and their use has not increased since 2004. This observation is not entirely clear, as calcium antagonists are very effective in lowering BP, have no detrimental metabolic effects and may be superior to other agents in stroke prevention (Citation4,Citation18,Citation45,Citation46). Previous publications regarding short acting calcium antagonists, which showed increased cardiovascular morbidity and mortality (Citation47–49), and high rate of malignancy (Citation50,Citation51), along with the high rate of ankle edema and reduced level of evidence regarding CHF and MI prevention of calcium antagonists in comparison with RAS blockers and diuretics (Citation46,Citation52), may have influenced Israeli physicians to prescribe calcium antagonists at a lesser rate. It is noteworthy that the use of calcium antagonists increased with age and elderly subjects were more likely to be treated with these drugs, as recommended by the NICE (Citation8).
In our cohort, women were treated with more antihypertensive agents suggesting a higher awareness of hypertension treatment in women, similarly to other surveys of hypertensive patients (Citation11). We also show that between 2004 and 2010 there was an increased trend to use combinations of three or more antihypertensive agents. This trend is in accordance with the understanding that in many patients combination therapy is required to control BP.
Strengths and limitations
Our study is based on a comprehensive nationwide registry of unselected patients. It has, however, several limitations. First, the study population, comprising patients admitted with an acute stroke or TIA, represents a specific patient group and not necessarily the total hypertensive population. However, since stroke is a major complication of hypertension and the baseline characteristics of our cohort are not unique to the stroke population, we believe that it still represents current treatment trends. Secondly, we do not have data on BP control prior to hospitalization and reasoning why medications were chosen. It is possible that specific drug classes were associated with side-effects or were contraindicated because of certain medical conditions, yet we believe that these numbers are considerably low, and the withdrawal rate is quite low, reaching 10%, as has been described in a recent meta-analysis (Citation52). Third, we included all classes of diuretics and calcium antagonists, yet the majority of the cohort has no reason for other diuretics than thiazide, and other calcium antagonist than dihydropyridines.
In conclusion, despite recent guidelines, Israeli physicians prefer RAS blockers and beta-blockers to other antihypertensive drugs, regardless of comorbid conditions, which may influence antihypertensive pharmacotherapy selection.
Acknowledgement
All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Conflict of interest: None.
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