the assignment is about how African American response to ACE inhibitor medication in hypertension. 1 page only and that needs to include: medication response and validate it with research and how the nurse advocate for the patient to have different medication). The paper needs to be in APA 7th Edition format including the references.
Intern Emerg Med (2016) 11:355–374
DOI 10.1007/s11739-016-1422-x
IM – REVIEW
Systematic review: antihypertensive drug therapy in patients
of African and South Asian ethnicity
Lizzy M. Brewster1,2 • Gert A. van Montfrans1,2 • Glenn P. Oehlers3
Yackoob K. Seedat4
•
Received: 9 December 2015 / Accepted: 22 February 2016 / Published online: 30 March 2016
Ó The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Despite the large differences in the epidemiology of hypertension across Europe, treatment strategies are
similar for national populations of white European descent.
However, hypertensive patients of African or South Asian
ethnicity may require ethnic-specific approaches, as these
population subgroups tend to have higher blood pressure at
an earlier age that is more difficult to control, a higher
occurrence of diabetes, and more target organ damage with
earlier cardiovascular mortality. Therefore, we systematically reviewed the evidence on antihypertensive drug
treatment in South Asian and African ethnicity patients. We
used the Cochrane systematic review methodology to
retrieve trials in electronic databases including CENTRAL,
PubMed, and Embase from their inception through
November 2015; and with handsearch. We retrieved 4596
reports that yielded 35 trials with 7 classes of antihypertensive drugs in 25,540 African ethnicity patients. Aside
from the well-known blood pressure efficacy of calcium
channel blockers and diuretics, with lesser effect of ACE
inhibitors and beta-blockers, nebivolol was not more
effective than placebo in reducing systolic blood pressure
levels. Trials with morbidity and mortality outcomes indicated that lisinopril and losartan-based therapy were associated with a greater incidence of stroke and sudden death.
Furthermore, 1581 reports yielded 16 randomized controlled
trials with blood pressure outcomes in 1719 South Asian
hypertensive patients. In contrast with the studies in African
ethnicity patients, there were no significant differences in
blood pressure lowering efficacy between drugs, and no
trials available with mortality outcomes. In conclusion, in
patients of African ethnicity, treatment initiated with ACE
inhibitor or angiotensin II receptor blocker monotherapy
was associated with adverse cardiovascular outcomes. We
found no evidence of different efficacy of antihypertensive
drugs in South Asians, but there is a need for trials with
morbidity and mortality outcomes. Screening for cardiovascular risk at a younger age, treating hypertension at lower
thresholds, and new delivery models to find, treat and follow
hypertensives in the community may help reduce the excess
cardiovascular mortality in these high-risk groups.
Keywords Hypertension Antihypertensive drugs
Systematic review African continental ancestry group
South Asian Ethnic groups
& Lizzy M. Brewster
l.m.brewster@amc.uva.nl
1
Department of Vascular Medicine, F4-222, Academic
Medical Center, University of Amsterdam, Meibergdreef 9,
1105 AZ Amsterdam, The Netherlands
2
Department of Internal Medicine, Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands
3
Department of Cardiology, Academic Hospital of
Paramaribo, Paramaribo, Suriname
4
Nelson R Mandela School of Medicine, Faculty of Health
Sciences, University of KwaZulu Natal, Private Bag. 7,
Congella, 4013 Durban, South Africa
Background
The increasing ethnic diversity of the European population
is likely to bring a greater diversity in disease and disease
patterns to the doctor’s office. Around 33 million immigrants live in the European Union. It is estimated that a
third of these immigrants are from other European countries, while immigrants from non-European countries are
mainly African (25 %, with more than half North-African),
or Asian (21 %) [1].
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356
Despite the large differences in the epidemiology of
hypertension across Europe [2], treatment strategies tend to
be similar for national populations of white European
descent. Nevertheless, in particular patients of South Asian
and sub-Saharan African descent tend to have more
hypertension and diabetes, and more target organ damage
and cardiovascular mortality at a younger age than patients
of white European descent. In addition, hypertension
occurs earlier in life in these patients groups, bringing
about a faster progression from normotension to hypertension, with higher mean blood pressures than in white
patients [3–22].
While little is reported regarding the pathophysiology of
hypertension in South Asian patients, abundant data in
patients of African descent indicate there is greater salt
sensitivity, blunted nocturnal dipping, and enhanced
vasoconstriction in this group [3–8, 10, 12–14, 16–21].
South Asians are genetically diverse, but members of this
population subgroup share a high cardiovascular risk, with
more severe atherosclerosis reported, and ischaemic end
organ damage at a younger age even with lower cholesterol
levels than in whites [11]. Thus, hypertension seems to be a
more aggressive disease, occurring at a younger age in
these patient groups. This could have important implications for hypertension screening and management.
In patients of all ethnicity groups, non-pharmacological
intervention to reduce hypertension and cardiovascular
risk, including dietary adjustments, physical exercise,
weight reduction, smoking cessation, and reduction of
excessive alcohol intake should be part of hypertension
management. In addition, stress reduction and relaxation
exercise might aid in reducing blood pressure [23]. In
particular, diets high in potassium and calcium and low in
sodium, such as the (DASH) diet, have documented blood
pressure lowering efficacy [24–30]. These measures are
thought to be effective in hypertensives across ethnic
groups, but increasing evidence indicates that the very low
salt intake (\1500 mg or \65 mmol sodium per day)
recommended for persons of African ethnicity [31–33], has
been associated with increased mortality in this group,
potentially related to activation of the renin angiotensin
system [31, 32]. Even so, high salt intake ([2300 mg or
[100 mmol sodium per day) is still considered detrimental
to cardiovascular health [32], and moderate salt restriction
continues to have a place in the management of hypertension in all ethnic groups.
However, most patients with hypertension will need
drug therapy aside life style measures. Therefore, in this
paper, we review the evidence on randomized trials of
antihypertensive drug treatment in African and South
Asian ethnicity patients, and propose practical approaches
for the European situation.
123
Intern Emerg Med (2016) 11:355–374
Methods
The participation of patients of ethnic minority groups in
major, international clinical trials is generally too low to
calculate the primary outcome with sufficient power [34].
Therefore, we systematically reviewed the evidence on the
efficacy of antihypertensive drug therapy to reduce blood
pressure and morbidity and mortality outcomes, and pooled
the existing data.
Systematic searches were conducted in November 2015,
with our previous systematic review on patients of African
ethnicity [16, 17] updated and expanded. In brief, we used
the Cochrane systematic review methodology, [35] and
defined a highly sensitive search strategy to retrieve original reports of randomized controlled trials in hypertensive
African and South Asian ethnicity patients, providing
original quantitative data on the effect of antihypertensive
monotherapy on blood pressure (trial duration at least
2 weeks) vs concurrent placebo treatment, or antihypertensive mono or combination therapy on morbidity or
mortality outcomes (trial duration at least 1 year).
We included only trials with major drug classes in
adults, men and non-pregnant women, with uncomplicated
primary hypertension (no history of, or current cardiovascular events or ESRD). Trials that considered oral antihypertensive treatment with thiazide and thiazide-like
diuretics, calcium-channel blockers, centrally acting
agents, peripheral adrenergic neuron antagonists, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin
II receptor blockers were eligible for inclusion.
We conducted separate searches and data analysis for
these two ethnic groups. Searches were performed in
electronic databases (Embase, PubMed, Cochrane Library
CENTRAL, Literatura Latino-Americana y del Caribe en
Ciencias de la Salud (LILACS), African Index Medicus,
and for South Asian patients, IndMED) from their inception through November 2015, without language restriction.
These databases have different software and therefore
different search languages, but a typical search strategy for
trials in patients of African ethnicity was, ‘‘(Black* OR
Afri* OR AFRO* OR Creole OR Carribean OR Caribbean
OR negr* OR ethnic* OR blacks) AND (hypertension OR
antihypertensive) AND randomized’’; and for South
Asians: the first step was ‘‘(South Asian OR South Asians
OR India OR Indian OR Hindustani OR Bangladesh OR
Nepal OR Sri Lanka OR Ceylon OR Pakistan)’’.
Search yields from all databases were considered and
analysed separately to prevent merging errors and to
enhance trial retrieval. Furthermore, we contacted experts
and performed hand search. We did not include trials in
diabetics only, with experimental drugs, or with complementary medicines.
Intern Emerg Med (2016) 11:355–374
We used data extraction forms to collect trial data. With
pilot searches, we retrieved very few placebo controlled trials
in South Asians, and decided to review drug vs drug trials in
this group. For drug vs drug trials with multiple treatment
arms, we followed the Cochrane handbook methodology and
combined the comparison groups into one group of ‘‘other
drugs’’ [35]. African or South Asian descent (ancestry, or
ethnicity) were defined as respectively of sub-Saharan African
descent, or Indian subcontinental descent as indicated by the
authors. We included only randomized controlled trials, and
methodological quality was further assessed using the Jadad
score, based on the description of randomization, blinding, and
accountability of all patients, including withdrawals in each of
the study groups, and the underlying reasons. Subgroups were
based on gender and geographical location, and compliance
data were assessed in trials with mortality outcomes.
Statistical analysis
Quantitative analysis of outcomes was based on intention-totreat results (primary) and per protocol analysis (secondary).
We included data from the first part of crossover studies
when such data were available; if not, we included the data
these studies provided. Our measure of effect for each study
was difference in means (in mmHg) for systemic arterial
blood pressure (continuous measure) and relative risk (RR)
for dichotomous data. In addition, we calculated achievement of target diastolic blood pressure (DBP\90 mmHg, or
reduction of C10 mmHg, or C10 %, as defined by the
author) as the weighted mean of placebo-corrected results per
drug class, or in South Asians, vs other drug types.
Missing standard deviations were imputed per drug
class. We clinically assessed studies for heterogeneity in
patient characteristics, interventions, and outcomes, to
decide whether studies should be pooled. Furthermore, we
used I2 statistics to quantify the proportion of total variation in the estimates of treatment effect that was due to
heterogeneity. We planned to not aggregate results with a
high variation across studies (I2 C 75 %) [17, 35]. When
we aggregated studies, we conservatively used the random
effects model to estimate the average intervention effect.
Data in square brackets are 95 % confidence intervals,
unless indicated otherwise. We used Review Manager
(RevMan) software, version 5 (Cochrane Collaboration,
Oxford, UK) for the analyses.
Results
Patients of African ethnicity
Full reports or abstracts from 4596 references of papers
yielded 35 trials with 7 classes of antihypertensive drugs, in
357
25,540 patients. Blood pressure was the main outcome
measure in 28 of these trials (Figs. 1, 2; Table 1) [36–66],
and morbidity or mortality in seven trials (Table 2) [67–
88]. Our 2015 update included two new trials with blood
pressure outcomes on nebivolol [46, 53], and eight new
reports on morbidity and mortality outcomes (five reports
with new subgroup analyses from the ALLHAT and LIFE,
and AASK trials, and three new reports of the VALUE,
INVEST, and ACCOMPLISH trials) [81–88]. Trials were
clinically comparable in describing the results of randomized controlled interventions with antihypertensive drugs in
African ethnicity patients with hypertension, but the age
range, inclusion blood pressure, drugs and drug dose varied
(Tables 1, 2). Since we retrieved only two new blood
pressure trials considering monotherapy with nebivolol vs
placebo, the results of the 2015 update are similar to the
data reported previously, as depicted in Fig. 2a, b. As a
post hoc outcome, nebivolol was analysed separately as
well because of the presumed different mechanism of
action [46, 53]. Nebivolol is thought to enhance nitric
oxide generation [46, 53]. However, the pooled weighted
mean difference in systolic (SBP) and diastolic pressure vs
placebo of these two trials is respectively SBP
-3.38 mmHg, 95 % CI [-8.38; 1.62]; I2 33 %; and DBP
-5.00 mmHg, 95 % CI [-7.41; -2.59] (I2 = 0 %). With
the addition of these relatively large trials to the pooled
analysis (Fig. 2a) the size of the effect of beta-adrenergic
blockers on systolic blood pressure was similar, but the
confidence interval became narrower, and statistically
significant from placebo [pooled estimate for systolic blood
pressure without nebivolol -3.53 [-7.51; 0.45]
(I2 = 50 %) [17], and with nebivolol -3.73 [-6.80;
-0.66] (I2 = 44 %), Fig. 2a].
Achievement of target DBP differed by drug class,
calcium-channel blockers 46 % (RR 3.39 [2.35; 4.90];
diuretics 31 % (RR 2.49 [1.68; 3.69]; beta-adrenergic
blockers 24 % (RR 1.97 [1.43; 2.72]; centrally acting
agents 23 % (RR 2.22 [1.35; 3.63]; angiotensin II receptor
blockers 19 % (1.77 [1.41; 2.21]; alpha-blockers 13 % (RR
1.71 [1.02; 2.86]; and ACE inhibitors 10 % (RR 1.35 (0.81;
2.26); with a RR of [1.0 indicating a beneficial effect.
Thus, the aggregated data show a greater effect of calcium blockers and diuretics, while beta-adrenergic blockers
and ACE inhibitors are the least effective drugs to lower
SBP and DBP, respectively. The cause of these differences
in drug responses is largely unknown. Our findings are in
accord with the suppressed activity of the renin-angiotensin-aldosterone system in hypertensive patients of
African ethnicity, and the high activity of creatine kinase,
promoting vasoconstriction and salt retention [8, 16]. As a
consequence, patients of African ethnicity are significantly
less sensitive to drugs that block the renin-angiotensinsystem (angiotensin-converting enzyme inhibitors and
123
358
Fig. 1 Trial flow: patients of
African ethnicity. Asterisk with
results for African ethnicity
patients in the Materson [47,
48], TAIM [57, 58], TOMHS
[59, 60], SHEP ([68] and
unpublished report), AASK [75,
76, 81] and ALLHAT [79, 80,
86, 88]; LIFE [73, 85, 87]
studies contained in more than
one report. Most excluded
papers were not an RCT; and of
the RCT’s retrieved, most were
either not an RCT in
hypertensives, or an RCT’s in
other ethnic groups, an RCTs
with combination therapy, drug
vs drug trials, or in particular for
morbidity and mortality trials,
multiple overlapping reports
concerning these trials
Intern Emerg Med (2016) 11:355–374
Reports retrieved in databases
(n = 4596)
Excluded reports (n = 4511)
No original report of an RCT with
anhypertensive drug therapy in hypertensive
adult men or non-pregnant women of African
ethnicity
Eligible reports
(n = 85)
Excluded eligible trials (n = 44)
No quantave outcome data for African
ethnicity paents (n = 31)
Separate data of responders to therapy (n = 1)
Blood pressure and other data unclear (n = 1)
Double study entry within a database (n = 1)
Overlap in published data (n = 10)
Included reports
(n = 41; trials n = 33)
Non-electronic search (contact with
authors, hand searching) (n = 5)
Results for African ancestry paents
in TAIM (58) , TOMHS (60), VALUE
(82), and INVEST (83) studies;
unpublished results SHEP study,
Total included reports
(n = 46; trials n = 35)*
Blood pressure trials (n = 28)
Morbidity/mortality trials (n = 7)
angiotensin II receptor blockers) and beta-blockers [16].
Genetic and pharmacokinetic differences do not fully
explain these differences [16], but altered cellular functions
based on high creatine kinase activity and enhanced
phosphoryl group buffer function have been implied in this
group, leading to enhanced ATP-dependent responses
including greater contractility, salt retention and therapy
failure [16, 18], as well as lower NO bioavailability [8, 16].
We predefined subgroups based on gender and on geographical location. However, only 3 small trials out of 28
trials with blood pressure outcomes reported data for men
123
and women (N = 146 patients), and this was not further
analysed [40, 45, 66]. When we separately analysed US/
Caribbean studies, calcium-channel blockers changed SBP
by -11.89 mmHg (CI -14.12 to -9.67 mmHg) and betablockers led to a change of -4.83 mmHg (CI -7.91 to
-1.75 mmHg); the size of the effect of alpha-blockers on
DBP became heterogeneous. When we separately analysed
data from African studies, however, only calcium-channel
blockers remained more effective than placebo for all
outcomes analysed. Diuretics did not significantly differ
from placebo in achieving the DBP goal (relative risk 3.55
Intern Emerg Med (2016) 11:355–374
[CI 0.41–31.05]), and ACE inhibitors, beta-blockers, and
alpha-blockers did not significantly differ from placebo in
reduction of SBP and DBP. None of the African studies
used a cutoff baseline DBP of less than 114 mmHg,
compared with 7 of the 15 US and Caribbean studies
(Table 1). Thus, we could not determine whether the
response of African patients truly differed from that of US
and Caribbean patients or was rather related to higher
baseline blood pressure levels.
We retrieved seven trials with morbidity and mortality
outcomes (Table 2) [67–88]. Most included patients were
older than 50 years with risk factors for cardiovascular
disease, followed for 3–5 years, with cardiovascular events
and mortality as main outcome measures. The Jadad scores
ranged from 1 to 5 (Table 2). An average of three drugs
was needed in an add-on strategy to reach blood pressure
goals as defined in the trials. The majority of African
descent participants (50–70 %) reached blood pressure
control, but 95 % needed combination therapy. In line with
the blood pressure lowering efficacy of monotherapy, more
patients on calcium blocker-based treatment reached goal
blood pressure, while there was a reduced blood pressure
lowering response in treatments based on initial
monotherapy with angiotensin II receptor blockers or ACE
inhibitors [82, 83, 86].
There was no statistical difference between the different
treatment arms in primary morbidity and mortality outcomes (Table 2). The main side effects of long-term therapy were newly developed diabetes (diuretics [ calcium
blockers [ ACE inhibitors), and a significantly greater
occurrence of cough and angioedema with ACE inhibitors,
72 per 10,000 (0.72 %), vs diuretics (0.04 %), and calcium
blockers (0.06 %) for African ethnicity patients in ALLHAT [17, 86].
In the SHEP study, the overall effect of diuretics on the
primary outcome stroke in African ethnicity patients was
not significantly different from placebo. In subgroup
analysis, stroke risk reduced in women of African ethnicity
(relative risk 0.36 [CI 0.16; 0.83]) but not in men (relative
risk 0.98 [CI 0.39; 2.44]) [69]. However, treatment did
reduce cardiovascular events as a secondary outcome
(hazard ratio for all cardiovascular events, 0.50 (CI 0.32;
0.78) (unpublished results, SHEP trial investigators).
Furthermore, in the ACCOMPLISH trial, there was no
significant difference in African ethnicity patients between
the two treatment strategies in retarding the rate of progression of kidney disease, in contrast to patients of other
ethnicities where amlodipine/benazepril-based therapy was
more effective than hydrochlorothiazide/benazepril [84].
Although ACE inhibitor-based treatment yielded better
clinical outcomes in kidney disease in the AASK trial [75],
there was no difference in prevention of cardiovascular
events by drug type [81], while the results of the ALLHAT
359
trial indicates that cardiovascular morbidity outcomes were
worse with treatments based on inhibitors of the renin
angiotensin system [86]. The use of lisinopril initiated
treatment vs chlorthalidone in patients of African ethnicity
was associated with a relative greater risk of morbidity:
combined CHD (1.15 [1.02; 1.30]), combined CVD (1.19
[1.09; 1.30]), stroke 1.40 [1.17; 1.68], angina 1.24 [1.07;
1.44]. Heart failure risk was lower with chlorthalidone
[86]. No data were provided for lisinopril vs amlodipine.
In line with these findings with ACE inhibitors, the
LIFE study showed that losartan-initiated therapy was
superior to atenolol-initiated therapy in reducing stroke risk
in hypertensive patients of European descent. However,
among patients of African descent, losartan-initiated
treatment was associated with a nearly significant increase
in stroke events compared with atenolol unadjusted hazard
ratio, 1.99 [1.00; 3.98] [85], similar to the findings of the
primary outcome, a composite outcome including stroke
[17, 73]. In addition, the risk for sudden death was 97 %
higher in patients of African descent in the LIFE trial, with,
at this relatively small sample size (n = 533) a trend
towards increased risk with losartan [87]. These data
indicate that therapy initiated with blockers of the reninangiotensin-system is associated with a greater cardiovascular morbidity and mortality in patients of African
ethnicity.
We defined subgroups based on gender and based on
geographical location for morbidity and mortality outcomes. However, morbidity and mortality trials were
conducted in the USA only or included only a very small
number of non-USA patients (Table 2). The SHEP trial’s
outcome for men and women is discussed above, with
diuretics not significantly different from placebo in preventing stroke in African ethnicity men. In ALLHAT, men
of African descent had the highest absolute stroke risk
(mean 6 year rate/100 patients 7.73, 5.90, 5.81, and 5.90, in
African ethnicity men, women, and white men, women
respectively) and the highest stroke risk with lisinopril of
all sex-ethnic groups (6 year rate/100 patients for lisinopril
9.41, 7.25, 5.32, and 5.59, respectively) [88]. Furthermore,
pharmacogenetics outcomes differed by gender in the
AASK trial, only women randomized to a usual blood
pressure goal (mean arterial pressure 102–107 mmHg), and
with an A allele at CYP3A4 A392G, were more likely to
reach a target MAP of 107 mmHg [adjusted hazard ratio of
AA/AG compared to GG 3.41 (95 % CI 1.20–9.64;
P = 0.02)]. Among participants randomized to a lower
MAP goal, men and women with the C allele at CYP3A4
T16090C were more likely to reach the target MAP of
107 mmHg [adjusted hazard ratio 2.04 (95 % CI
1.17–3.56; P = 0.01)]. In addition, the polymorphisms
Arg65Leu, Ala142Val, and Ala486Val of the G proteincoupled receptor kinase gene, GRK4, were studied in the
123
360
AASK Study. Only in men randomized to the usual blood
pressure goal (mean arterial pressure 102–107 mmHg), the
adjusted ‘‘hazard’’ ratio to reach the goal blood pressure
with metoprolol was 1.54 (95 % CI 1.11–2.44; P \ 0.01)
with Ala142Val. There was no association between GRK4
polymorphisms and blood pressure response to metoprolol
in women [16].
Compliance data by ethnicity were only available for the
AASK study. Based on self-reported data and pill counts,
23 % of the patients had at least one noncompliant event,
non-adherence events (%) per patient year respectively
were 7.7, 6.6, and 7.1 for metoprolol, ramipril and
amlodipine [74–76].
As approaches to the management of cardiovascular
disease risk need to integrate assessment and treatment of
several risk factors, we describe the outcome of the lipid
lowering treatment arm of the ALLHAT trial (ALLHATLLT) [89]. Patients of African ethnicity have been underrepresented in prior trials addressing the effects of
cholesterol lowering. Participants treated for hypertension
in ALLHAT were eligible for inclusion in ALLHAT-LLT
when fasting LDL-C levels were 120–189 mg/dL
(3.1–4.9 mmol/L) or 100–129 mg/dL (2.6–3.3 mmol/L)
respectively for those with and without known coronary
heart disease. The primary outcome was all-cause mortality
in patients randomized to pravastatin 20–40 mg vs usual
care (respectively n = 1769 vs n = 1722 African ethnicity
patients). Vigorous cholesterol lowering therapy was discouraged in the usual care group, therefore the majority of
these patients did not receive lipid lowering drugs (90 % in
the second year to 72 % in the sixth year of the trial). There
was no difference in the primary outcome of all-cause
mortality between pravastatin and usual care (RR for
African ethnicity patients 1.01 [0.85–1.19]). In other outcomes, the relative risk for atherosclerotic coronary heart
disease events with pravastatin was lower in patients of
African descent than in other patients (RR 0.73 [0.58–0.92]
vs 1.02 [0.81–1.28]; P = 0.03). However, there was a
significantly greater stroke risk with pravastatin in patients
of African descent (RR 1.12 vs 0.74 in other patients,
confidence intervals not reported; P = 0.03). As a result,
there was no significant effect of pravastatin treatment on
combined cardiovascular disease outcomes in hypertensive
patients of African ethnicity [89].
Patients of South Asian ethnicity
With electronic searches (November 2015) we retrieved
1578 papers. We additionally retrieved three trials with hand
search, which were not eligible for inclusion. Sixteen randomized controlled trials were included, with blood pressure
as the main outcome. Only one trial was placebo controlled,
other trials assessed monotherapy with a drug from one drug
123
Intern Emerg Med (2016) 11:355–374
Fig. 2 Effect of different antihypertensive drugs on blood pressure inc
patients of African ethnicity. a Systolic blood pressure. b Diastolic
blood pressure. a, b Our previous review [17] was updated
(November 2015). Except for two nebivolol studies [46, 53], no
new trials with single drugs vs placebo and blood pressure outcomes
were retrieved. Random, random-effects model. Results are reported
as weighted mean differences in reduction of systolic and diastolic
blood pressure (mmHg) from baseline to endpoint with the use of
different antihypertensive drugs compared to placebo. Squares are
weighted mean differences in reduction of SBP/DBP (mmHg). The
size of the squares represents study weight, and horizontal lines
represent 95 % CIs. Arrowheads depict data outside the scale. When a
study provided only the placebo-drug difference, we entered a ‘‘nil’’
for placebo results. Results for Materson and colleagues’ study and
Weir and colleagues’ study are weighted means of older and younger
people and patients receiving a high and a low-salt diet, respectively.
Black diamonds are pooled estimates. Results for calcium-channel
blockers were not pooled because the size of the effect was
heterogeneous. ABC Association of Black Cardiologists, TAIM Trial
of Antihypertensive Interventions and Management, TOMHS Treatment of Mild Hypertension Study, TROPHY Treatment in Obese
Patients with Hypertension [36–66]
class vs a drug from another class. We did not include trials
that only compared drugs within one antihypertensive drug
class. The 16 included trials (Fig. 3; Table 3) were 4 weeks
to 9 months duration (median 8 weeks), containing original
data of 6 classes of antihypertensive drugs in 1719 South
Asian hypertensive patients without a history of, or current
cardiovascular events (n = 37 diabetics) [55, 90–104].
Blood pressure at inclusion was generally between 140
and 180 mmHg systolic, and 90 to 110 mmHg diastolic.
Most trials were conducted in India. The methodological
quality of the trials was less than in the African patients,
with the Jadad scores between 1 and 4 (median 2). No trial
had a Jadad score of 5, and only 2 were double blinded.
Most trials reported side effects and drop outs, but intention-to-treat analysis was used in only one (Table 3).
There were no significant differences between drug
classes in blood pressure-lowering efficacy, as analysed per
comparison presented in the trial data [35], (data not
shown). Calculation of the blood pressure lowering effect
per drug class was hampered by the limited data and
heterogeneity that could not be well accounted for (partly
due the small number of trials). However, South Asians
ethnicity patients represent a population subgroup where
the average effect is of clinical relevance. Therefore, we
allowed for heterogeneity in an a posteriori analysis, and
used the random effects model to calculate the inverse
variance-weighted mean blood pressure lowering effect of
the different drug classes (Table 4) [35].
Other effects described included that lisinopril reduced
micro-albuminuria (-33 vs -10 % in amlodipine) [95],
while diuretics and beta-adrenergic blockers were reported
to have the well-known metabolic side effects on lipid and
glucose metabolism. Non-diuretic, non-beta-adrenergic
Intern Emerg Med (2016) 11:355–374
a. Systolic blood pressure
Treatment
Study
n
mean (SD)
361
Placebo
n
mean (SD)
WMD
(95% CI Random)
Weight
WMD
%
(95% CI Random)
Comparison: 01 Calcium channel blockers
Fadayomi et al. (40)
15
–58.5 (13.9)
15
–0.2 (17.4)
17.7
–58.30 [–69.57;–47.03]
Materson et al. (47)
90
–14.6 (8.4)
88
–1.8 (10.5)
21.8
–12.80 [–15.60;–10.00]
Moser et al. (50)
35
–12.3 (11.1)
33
–0.9 (11.1)
21.0
–11.40 [–16.68;–6.12]
TOMHS (60)
16
–7.9 (11.1)
47
0.0 (11.1)
20.5
–7.90 [–14.20;–1.60]
Weir et al. (65)
24
–12.1 (13.2)
13
0.0 (13.2)
19.1
–12.10 [–21.01;–3.19]
Test for heterogeneity chi square=64.67 df=4 p
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