Proton-Pump Inhibitors Therapy and Blood Pressure Control

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DOI: 10.7439/ijpr.v4i3.116
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Abstract
Objective: To evaluate the potential impact of inhibitors of proton-pump in blood-pressure. .Methods: In a 24-hour-ambulatory-blood-pressure-monitoring (AMBP)-database we analyzed records of 462-hypertensive-patients according Proton-Pump Inhibitors (PPI). 150(33%)-patients were regularly users of PPI, and 312(67%) nonusers of PPI. Ambulatory-blood-pressure was measured non-invasively for 24--hours by the Spacelab-devices programmed-to-measure every 20-minutes during-daytime and every 60-minutes during-nighttime.Results: Systolic-blood-pressure(SBP) was lower in the Proton-Pump-Inhibitors (PPI)-group (135±20.vs.139±16mmHg, p=0,02) as well as diastolic-blood-pressure (DBP) (76±10.vs.83±10mmHg, p<0.001). Multivariate-analysis showed that use of beta-blocker(OR, 2.60) and PPI(OR, 2.70), were independently associated with blood-pressure-control.Conclusions: This study shows that concomitant PPI therapy in hypertensive-patients was associated with a small but statistically significant-reduction in 24-hours-BP, even after multivariate-adjustment. However, This statistical difference seems to lack clinical relevance.
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International Journal of Pharmacological Research www.ssjournals.com
ISSN: 2277-3312 Journal DOI:10.7439/ijpr
IJPR Volume 4 Issue 3 (2014) 142
Proton-Pump Inhibitors Therapy and Blood Pressure Control
Pedro Joya-Vazquez1, M Asuncion Bacaicoa2, Raul Velasco1, Jose L. Chicon1, Sara Trejo1,
M. Antonia Carrasco2, N. Roberto Robles3 and Juan F. Sanchez Munoz-Torrero*1
1Internal Medicine. H. San Pedro Alcántara. Cáceres. Spain
2Centro Salud Manuel Encinas. Cáceres. Spain
3Nephrology. H. Infanta Cristina. Badajoz. Spain
Corresponding author*:
Juan F Sánchez Muñoz-Torrero.
Servicio de Medicina Interna.
Hospital San Pedro de Alcántara.
Avda Pablo Naranjo s/n. 10004-Cáceres. Spain
E-mail: juanf.sanchezm@gmail.com
1. Introduction
Blood Pressure (BP) is an important biologic parameter that is predictive of cardiovascular outcome1. Evidences
from randomized trials have shown that effective antihypertensive treatments reduce cardiovascular morbidity and
mortality2. However, community-based studies show that blood pressure goals are achieved in only 25 to 40% of the
patients who take antihypertensive drug treatment2,3. It is estimated that roughly half of deaths due to coronary heart
disease can be attributed to sub-optimal BP control1. The investigation of factors which have an influence on BP control
has a relevant interest.
A variety of therapeutic agents or chemical substances can induce a transient or persistent change in blood
pressure, or they can interfere with the blood pressure-lowering effects of antihypertensive drugs3. Some experimental
studies have suggested that Proton-pump inhibitors (PPI) could play a role in blood-pressure (BP) reduction3,4,5. Moreover,
since PPI are used for long periods on prevention of digestive hemorrhage in cardiovascular patients who use the
antithrombotic therapy6,7 PPI must be taken into account for potential drug-drug interactions.
The potential role they may have PPI in patients at high cardiovascular risk in whom an adequate BP control is
even more important is unknown. Often patient’s polymedicated by the complexity of diseases intercurrents, that could
also interferes or dilute with the potential pleiotropic effects. We study hypertensive patients according IBP therapy, and
investigate the effect of PPI on BP using ABPM 24 hours in all cases.
2. Patients and Methods
In this transversal study, we analyze clinical data which were stored in a database of patients over 18 years
old with diagnosis of essential hypertension and therapy of antihypertensive drugs. These data were analyzed by ABPM.
Patients were divided in two groups: those who use PPI and those who do not use it. All patients provided written consent
to the participation in the record according to the requirements of the ethics committee within each hospital. All ethics
committees from all hospitals approved the study. Inclusion criteria were: Medical suspicion of white-coat hypertension or
drug resistant hypertension, and exclusion criteria: pregnant women or patients who do not follow the treatment. The study
included 462 patients from 492 patients recruited. Mean age was 59±12 years, 259 were men (56%). A prospective
surveillance of BP was performed.
Abstract
Objective: To evaluate the potential impact of inhibitors of proton-pump in blood-pressure. .
Methods: In a 24-hour-ambulatory-blood-pressure-monitoring (AMBP)-database we analyzed records of 462-
hypertensive-patients according Proton-Pump Inhibitors (PPI). 150(33%)-patients were regularly users of PPI, and
312(67%) nonusers of PPI. Ambulatory-blood-pressure was measured non-invasively for 24--hours by the Spacelab-
devices programmed-to-measure every 20-minutes during-daytime and every 60-minutes during-nighttime.
Results: Systolic-blood-pressure (SBP) was lower in the Proton-Pump Inhibitors (PPI)-group (135±20.vs.139±16mmHg,
p=0, 02) as well as diastolic-blood-pressure (DBP) (76±10.vs.83±10mmHg, p<0.001). Multivariate-analysis showed that
use of beta-blocker (OR, 2.60) and PPI (OR, 2.70), were independently associated with blood-pressure-control.
Conclusions: This study shows that concomitant PPI therapy in hypertensive-patients was associated with a small but
statistically significant-reduction in 24-hours-BP, even after multivariate-adjustment. However, this statistical difference
seems to lack clinical relevance.
Keywords: Proton-Pump-Inhibitors, Blood-Pressure-Reduction, 24-hours Ambulatory-Blood-Pressure
Pedro Joya-Vazquez hai et al Research Article
IJPR Volume 4 Issue 3 (2014) 143
Participants underwent 24-h ABPM during the working day before the clinic visit. At ~08.00 hours, participants
were attached with an ambulatory BP monitor (90207 ABP monitor. Spacelabs Healthcare, Washington, USA) on the non-
dominant arm. The apparatus was programmed to measure BP at twenty min intervals during daytime (08.0022.00 hours)
and at sixty minutes intervals during nighttime (22.0008.00 hours). On average, the cuff successfully inflated 76% of the
time across all participants. Participants were asked to carry on with their daily activities but they have to stop moving and
have to be quiet during measurements. Also, during measurements, patients were asked to write down any abnormalities,
such as: headache, nausea, or feeling stressed on their ambulatory diary cards. Only patients with 20 or more successful
daytime readings were included. Patient instructions and monitors’ applications were performed by an experienced
researcher, who was trained in the procedures of blood pressure measurement. The researcher used a standardized protocol
based on the European Society of Hypertension guidelines (www.eshonline.org).
Patients, who took their daily treatment during 20 or more days per month, were considered good users of the
treatment. Variables were registered: sex, age, anthropometric measures, educational status, smoking history, alcohol
intake, exercise, records of cardiovascular disease, diagnosis’ date of hypertension, diabetes and time fr om diagnoses,
Metabolic Syndrome (ATP criteria), sleep apnea syndrome (objective diagnosis with a sleep study). Some biochemical
tests were performed: plasma lipids, Reactive C Protein and creatinine and urine albumin-to-creatinine ratio in the first
morning urine sample.
All data were expressed as the mean± standard deviation for continuous variables and as proportions for
categorical variables. The differences in the values of the variables between groups were tested with chi-square statistics or
t-test when appropriate. Logistic regression was used to examine the associations with BP control. BP control was defined
as 24-hour systolic <130 mm Hg and diastolic < 80 mm Hg. The models were adjusted for covariates, including age, sex,
diabetes, albumin-to-creatinine ratio, history of ischemic cardiovascular disease and received treatment (diuretic agent,
ACE inhibitor, ARB, or both, beta-blocker and three or more drugs for antihypertensive, antithrombotics drugs, statins,
oral antidiabetic drug, and PPI). These covariates were selected from univariate analysis. P<0.05 was considered to be
statistically significant. Data were analyzed using the SPSS, version 15.0 software package (SPSS Inc., Chicago, Illinois,
USA).
3. Results
PPIs users were 150 (32%), and their distribution was: omeprazole 114 (76%); esomeprazole 16 (11%);
lansoprazole 12 (8%); raveprazole 6 (4%), and pantoprazole 2 (1,3%) patients. Table 1 shows the baseline characteristics
of patients included in the study. PPIs users were older (63±11 years vs 56±12, p <0.001), there were more women (57%
vs 38%, p <0.001) and a lower proportion of patients with higher studies (12% vs 29%, p <0.001). No differences between
groups were observed according to body weight and smoking status. Use of PPI also was associated with previous records
of cardiovascular disease, 53 (35%) vs 36 (11%) of non PPIs users (p<0.001) (see table 1).
Also the number of treatments was different: 28 (36%) of PPIs users were taking 3 or more hypertension drugs vs.
29 (18%) of PPIs non users, p<0.01. The level of significance was maintained for the different class of antihypertensive
family. Antithrombotic treatments (anticoagulants and antiagregants) were used by 40 (52%) of PPIs users vs. 48 (30%) of
non users (p<0.01). Also statins use was more frequent among PPIs users, 55 (71%) vs. 83(51% p<0.01).
The table 2 shows mean BP in the ABPM study in the different groups. During 24h, SBP was lower in the PPIs
users group 135±20 vs. 139±16 mmHg in the other group, p=0,003) as well as 24h DBP 76±10 vs. 83±10 mmHg
(p<0.001). The average difference was 4 mmHg (SBP) and 7 mmHg (DBP), in the 24h lapse. Similar differences were
found during daytime (6 and 7 mmHg respectively) and during nighttime (3 and 5 mmHg). Significances are shown in
table 2. Adequate BP control (< 130/< 80 mmHg) was achieved in 63 (42%) for PPIs users vs. 67 (21%) for PPIs non users
(p<0.001).
The table 3 shows univariate and multivariate analysis results from the clinical and therapeutic characteristics in
relation to BP control achievement. Only two variables were independently associated with BP control in the ABPM (OR,
95%CI): use of beta-blocker 2.60 (1.23-5.45) and PPIs treatment, 2.70(1.50-4.82). On the other hand, albumin-to-
creatinine ratio >30 mg/dL, 0.41 (0.17-0.99), and ischemic cardiovascular disease record, 0.37(0.17-0.80) were negatively
associated with BP control.
Pedro Joya-Vazquez hai et al Research Article
IJPR Volume 4 Issue 3 (2014) 144
Table 1: Characteristics of patients regarding Proton-Pump Inhibitors therapy
No Proton-pump
inhibitors treatment
N=312
Proton-pump inhibitors
treatment
N=150
P value
Variable
Demographic characteristic
Male sex-no.(%)
Age-yr
University education
Clinical characteristic
Smoking history-no/total no.(%)
Never
Former
Current
Alcohol ingestion
Nothing
Daily intake-gr/24 h
Moderate or vigorous exercise#
History of ischemic cardiovascular disease
History of cerebrovascular disease
History of coronary artery disease
History of peripheral vascular disease
Time from hypertension diagnosis-yr
History of Diabetes Mellitus
Time from diabetes diagnosis-yr
Glycated hemoglobin-%
Body-mass index
Waist circumference: (men >102 cm, women >
88 cm)
Diagnosis of Metabolic Syndrome
Atrial Fibrillation
Sleep Apnea Syndrome
Laboratory results
Cholesterol-mg/dL
Total
LDL
HDL
Triglycerides-mg/dL
Reactive C Protein-mg/dL
Creatinine- mg/dL
Albumin-to-creatinine§ ratio. Level >30 mg/dL-
no. (%)
Medications-no. (%)
Diuretic agent
ACE inhibitor, ARB, or both
Calcium-channel blocker
Beta-blocker
3 or more drugs for hypertension
Antithrombotics drugs*
Statin
Antidiabetic drug&
194(62%)
56±12
92(29%)
64/324(20%)
94/324(29%)
166/324(51%)
226(72%)
27±19
200(60%)
36(11%)
18(5.6%)
15(4.8%)
15(4.8%)
9.1±8.9
53(17%)
8.9±7.7
6.1±1.0
30±5.1
144(53%)
98(31%)
12(3.8%)
33(11%)
192±39
115±36
52±14
132±90
3.2±6
0.91±0.2
32(13%)
89(28%)
172(55%)
75(24%)
40(13%)
56(18%)
90(29%)
156(50%)
74(24%)
65(43%)
63±11
18(12%)
22/154(14%)
38/154(25%)
94/154(61%)
114(76%)
37±19
82(52%)
53(35%)
32(35%)
20(13%)
19(13%)
9.4±8.4
45(30%)
7.2±7.1
6.1±0.9
30±5.8
75(54%)
43(29%)
22(15%)
17(11%)
195±38
115±37
53±13
131±71
3.0±2.8
0.95±0.4
23(24%)
68(45%)
106(71%)
61(41%)
39 (26%)
56(37%)
79(53%)
107(71%)
46(31%)
<0.001
<0.001
<0.001
NS
NS
NS
NS
NS
NS
<0.001
<0.01
<0.01
<0.01
NS
<0.01
NS
NS
NS
NS
NS
<0.001
NS
NS
NS
NS
NS
NS
NS
<0.05
<0.001
<0.01
<0.001
<0.01
<0.001
<0.001
<0.001
NS
Plus-minus values are means±SD. Percentages may not total 100 because of rounding.
# Defined as a score on the Physician-based Assessment and Counseling for Exercise (PACE) evaluation of 4 to 8, indicating moderate
exercise at least five time s per week to vigorous exercise at least 3 days at week for a least the previous 6 months.
ACE denotes angiotensin-converting enzyme. ARB angiotensin-receptor blocker.
The body-mass index is the weight in kilograms divided by the square of the height in meters.
§The ratio is based on measurement of albumin in milligrams and creatinine in grams.
*Aspirin, clopidogrel or vitamin K antagonists. &: Oral Antidiabetic drugs or insulin
Pedro Joya-Vazquez hai et al Research Article
IJPR Volume 4 Issue 3 (2014) 145
Table 2: Ambulatory Blood-Pressure Monitoring regarding Proton-Pump Inhibitors therapy
Blood-pressure- mm Hg
NoProton-pump inhibitors
treatment (N=312)
Proton-pump inhibitors
treatment (N=150)
p value
24-hour systolic
24-hour diastolic
Daytime systolic
Daytime diastolic
Nighttime systolic
Nighttime diastolic
24-hour control-n(%)*
139±16
83±10
142±16
86±11
131±18
75±10
67(21%)
135±20
76±10
136±20
79±10
128±21
70±10
63(42%)
0.02
<0.001
0.005
<0.001
0.05
<0.001
<0.001
Mean ± Standart Deviation. * Systolic Blood-Pressure <130 and Diastolic <80 (mm Hg)
Table 3: Patient clinical and therapy characteristics, for 24 hour blood pressure control
(univariate and multivariate analyses)
24 hour blood pressure
No 24 hour blood
pressure control
(N=332)
24 hour blood
pressure control
(N=130)
Univariate
analysis
control vs no
control
Multivariate
analysis
control vs no
control
n (%)
n (%)
Odds ratio
[95% CI]
Odds ratio
[95% CI]
207 (62)
134(41)
89(27)
197(59)
64(19)
107(32)
71(21)
151(45)
45(18)
24(4.2)
39(12)
47(14)
24(7.2)
20(6)
15(4.5)
100(30)
190(57)
100(30)
46(13)
70(21)
109(33)
175(53)
86(26)
87(26)
52(40)
65(52)
21(16)
74(57)
22(17)
34(26)
27(21)
45(35)
10(11)
10(7.7)
11(8.5)
42(32)
26(20)
15(11)
16(15)
57(44)
88(68)
36(28)
36(28)
42(32)
60(46)
88(68)
34(26)
63(48)
0.40(0.27-0.61)
1.58(1.04-2.39)
0.53(0.31-0.89)
0.90(0.60-1.35)
0.94(0.63-1.42)
0.74(0.47-1.17)
0.97(0.58-1.59)
0.63(0.42-0.97)
0.60(0.28-1.24)
0.86(0.43-2.01)
1.44(0.71-2.91)
0.35(0.21-0.56)
1.81(1.19-2.75)
1.57(1.02-2.40)
0.89(0.57-1.39)
2.57(1.56-4.24)
1.79(1.14-2.81)
1.75(1.16-2.65)
1.88(1.23-2.88)
1.01(0.64-1.61)
2.65(1.74-4.04)
0.63(0.35-1.15)
0.76(0.40-1.43)
-
-
-
-
-
0.60(0.32-1.10)
0.41(0.17-0.99)
-
-
0.37(0.17-0.80)
1.85(0.87-3.94)
1.19(0.62-2.32)
-
2.60(1.23-5.45)
0.68(0.27-1.72)
0.66(0.31-1.41)
1.27(0.66-2.43)
0.85(0.41-1.77)
2.70(1.50-4.82)
§ The ratio is based on measurement of albumin in milligrams and creatinine in grams.* Aspirin, clopidogrel or vitamin K antagonists. &.
Oral antidiabetic drugs or insulin
4. Discussion
The influence of drugs in BP is a well-known phenomenon. In general, drug-induced pressure increases are small
and transient. However it can be more pronounced in patients with preexisting hypertension, in patients with renal failure,
and in the elderly. On the other hand, some non-antihypertensive drugs like statins or rosiglitazone might lower systolic
blood pressure particularly in patients with high blood pressure3,4. The potential mechanisms by which PPIs therapy may
lower BP are unknown, and probably cannot be explained by a single simple mechanism. Like statins, PPI may exhibit a
variety of pleiotropic effects. Currently available data suggest that PPI may be associated with immunoregulatory effects,
osteoporosis-related fractures, Clostridium difficile associated diarrhea, community and hospital-acquired pneumonia and
refractory hypomagnesemia3,4. Regarding to regulatory effect on BP, experimental studies have demonstrated that PPI
may have a direct mechanism in the regulation of human vascular tone3,4,5. The vasorelaxant effects have been previously
demonstrated in artery rings isolated from experimental animals9-11. Omeprazole and lansoprazole both induced
Pedro Joya-Vazquez hai et al Research Article
IJPR Volume 4 Issue 3 (2014) 146
concentration-dependent, reversible and reproducible relaxations of human artery internal mammary. The mechanism of
this effect on arterial tree can be explained by the regulation of intracellular Ca2+.3,4 Other potential pathway involves PPI
interactions with cardiovascular drugs3,4. PPI are CYP2C9 and CYP2C19 moderate inhibitors which may reduce the
metabolism of the substrates of this pathways (i.e. losartan, torasemide or some beta-blockers) and serum concentrations
could increase3. In another side, other data do not support the fact that PPI use may have a significant and inmediate
impact on hemodynamic parameters in a high-risk intensive care setting17. However this has not been studied in patients
who were clinically stable in the daily practice.
The ABPM shows that patients who take PPI had a lower SBP and DBP than those who do not take PPI drugs.
The reduction of BP was similar in day and night values. These findings suggest that PPI therapy in hypertensive patients
may be associated with a small but significant reduction of the average blood pressure in 24 hours. However, this
reduction of less than 5 mmHg systolic BP not seems to be important enough to provide cardiovascular protection in the
subgroup of patients with advanced cardiovascular disease3. Whatever we do not know whether this effect could be
maintained steadily over time.
PPI users had ischemic cardiovascular disease, diabetes, atrial fibrillation or microalbuminuria more often than
nonusers. These patients are considered to be high risk patients, and current guidelines establish more aggressive
therapeutic objectives and the use of antithrombotic therapy which advise for the treatment with PPIs for preventing
digestive disease. This might suggest that PPI therapy is a bias result to an aggressive treatment in a highly motivated
group of patients, mostly after myocardial infarction. Although all patients have been recommended with a reduction of
salt intake in their diets, the monitoring of this recommendation should have been contrasted. Beside the previous stated, a
higher use of diuretics in the PPI group can make a significant difference in BP control.
The main limitation of this observational study is that it is based on a database of ABPM. We are aware that this
study does not provide the guarantees of a controlled prospective study and that this type of disease is an extremely
complex disease and there are many factors that can influence and beyond those provided in the analysis should be
thought. And what could be considered a bias is rather strength of the study. Because patients with major cardiovascular
damage are undoubtedly aware, are often better treatment compliers; promoting better control of blood pressure. It could
not to tip the balance towards a potential protective effect for the use of PPIs. And although, it seems undeniable
hypotensive effect of PPIs at least in the short term. Our study was unable to demonstrate that the differences could have a
beneficial clinical impact, as would have been desirable to find.
To date, know the publications of other studies that are intended to look at the impact of PPIs in controlling BP in
clinical practice are lacking. But perhaps the mayor interest of this trial is that we could assess the extent to which the use
of IBP through its hypotensive effect could have a clinically relevant protective effect of cardiovascular standpoint. When,
we were able to compare hypertensive patients with different degrees of cardiovascular damage. Moreover there are a lot
questions unanswered that remain. We do not know with certainty which could be the threshold needed in reducing SBP
and / or BDP and this value remains unchanged regardless of cardiovascular risk. If indication of IBP is common and
observations tend to emerge about unexpected benefits of the drug, and if a reasonable biologic rationale can be profferes,
trialists take the next logical step and devise a randomized, controlles trial to determine whether a causal relationship
clinical outcome can be shown.
This study offers insights into factors associated with better BP control with an unselected patient population, in
contrast to the rigorously controlled conditions of randomized clinical studies. It provides feedback from real-world
clinical situations. Probably our main issue is that our experience endorses the fact that PPIs could contribute to a better
control of BP in patients with cardiovascular risk. Encouraging conducting controlled studies that can respond to the many
questions raised.
In conclusion, this study raises the possibility that PPI therapy reduces the BP among patients with hypertension.
However, our findings do not support the hypothesis of this effect may provide cardiovascular protection. Possibly in part
to a diminished response of impaired vascular tree, by interaction with a greater number of drugs and certainly by factors
that we still are unknown.
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    Despite effective medications, rates of uncontrolled hypertension remain high. Treatment protocols are largely based on randomized trials and meta‐analyses of these studies. The objective of this study was to test the utility of machine learning of big data in gaining insight into the treatment of hypertension. We applied machine learning techniques such as decision trees and neural networks, to identify determinants that contribute to the success of hypertension drug treatment on a large set of patients. We also identified concomitant drugs not considered to have antihypertensive activity, which may contribute to lowering blood pressure (BP) control. Higher initial BP predicts lower success rates. Among the medication options and their combinations, treatment with beta blockers appears to be more commonly effective, which is not reflected in contemporary guidelines. Among numerous concomitant drugs taken by hypertensive patients, proton pump inhibitors (PPIs), and HMG CO‐A reductase inhibitors (statins) significantly improved the success rate of hypertension. In conclusions, machine learning of big data is a novel method to identify effective antihypertensive therapy and for repurposing medications already on the market for new indications. Our results related to beta blockers, stemming from machine learning of a large and diverse set of big data, in contrast to the much narrower criteria for randomized clinic trials (RCTs), should be corroborated and affirmed by other methods, as they hold potential promise for an old class of drugs which may be presently underutilized. These previously unrecognized effects of PPIs and statins have been very recently identified as effective in lowering BP in preliminary clinical observations, lending credibility to our big data results.
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    Coronary heart disease is the leading cause of death worldwide affecting millions of people in both developed and developing countries. The dual aims of this book are to review the well-established and emerging risk factors in coronary heart disease (CHD) and to apply this knowledge to public health approaches to disease prevention. The book includes authoritative accounts of studies within a single population and international studies, important areas of methodological development, trials to test preventive strategies, and the application of epidemiological and other knowledge to the development of public health policy for the prevention of widespread disease. It is an all-encompassing work containing contributions from the world authorities in the field. The book is divided into four sections. The introduction reviews advances in the understanding of, and the current status, of risk factors for CHD. Section Two looks at recent global trends and emerging patterns of CHD morbidity and mortality in several countries, and includes chapters on work done under the auspices of the World Health Organisation (WHO) on the global burden of disease in relation to smoking and blood pressure. Section Three focuses on advances in understanding the aetiology of CHD with each chapter focused on a particular risk factor. Section Four explores measures of prevention and intervention in terms of public health policy with specific examples from around the world.
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    Most patients with hypertension have essential hypertension or well-known forms of secondary hypertension, such as renal disease, renal artery stenosis, or common endocrine diseases (hyperaldosteronism or pheochromocytoma). Physicians are less aware of drug induced hypertension. A variety of therapeutic agents or chemical substances may increase blood pressure. When a patient with well controlled hypertension is presented with acute blood pressure elevation, use of drug or chemical substance which increases blood pressure should be suspected. Drug-induced blood pressure increases are usually minor and short-lived, although rare hypertensive emergencies associated with use of certain drugs have been reported. Careful evaluation of prescription and non-prescription medications is crucial in the evaluation of the hypertensive individual and may obviate the need for expensive and unnecessary evaluations. Discontinuation of the offending agent will usually achieve adequate blood pressure control. When use of a chemical agent which increases blood pressure is mandatory, anti-hypertensive therapy may facilitate continued use of this agent. We summarize the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action. Copyright © 2015. Published by Elsevier B.V.
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    In the Systolic Hypertension in the Elderly Program (SHEP) trial, conducted between 1985 and 1990, antihypertensive therapy with chlorthalidone-based stepped-care therapy resulted in a lower rate of cardiovascular events than placebo but effects on mortality were not significant. To study the gain in life expectancy of participants randomized to active therapy at the 22-year follow-up. A National Death Index ascertainment of death in the long-term follow-up of a randomized, placebo-controlled, clinical trial (SHEP) of patients aged 60 years or older with isolated systolic hypertension. Recruitment was between March 1, 1985, and January 15, 1988. After the end of a 4.5-year randomized phase of the SHEP trial, all participants were advised to receive active therapy. The time interval between the beginning of recruitment and the ascertainment of death by National Death Index (December 31, 2006) was approximately 22 years (21 years 10 months). Cardiovascular death and all-cause mortality. At the 22-year follow-up, life expectancy gain, expressed as the area between active (n = 2365) and placebo (n = 2371) survival curves, was 105 days (95% CI, -39 to 242; P = .07) for all-cause mortality and 158 days (95% CI, 36-287; P = .009) for cardiovascular death. Each month of active treatment was therefore associated with approximately 1 day extension in life expectancy. The active treatment group had higher survival free from cardiovascular death vs the placebo group (hazard ratio [HR], 0.89; 95% CI, 0.80-0.99; P = .03) but similar survival for all-cause mortality (HR, 0.97; 95% CI, 0.90-1.04; P = .42). There were 1416 deaths (59.9%) in the active treatment group and 1435 deaths (60.5%) in the placebo group (log-rank P = .38, Wilcoxon P = .24). Cardiovascular death was lower in the active treatment group (669 deaths [28.3%]) vs the placebo group (735 deaths [31.0%]; log-rank P = .03, Wilcoxon P = .02). Time to 70th percentile survival was 0.56 years (95% CI, -0.14 to 1.23) longer in the active treatment group vs the placebo group (11.53 vs 10.98 years; P = .03) for all-cause mortality and 1.41 years (95% CI, 0.34-2.61; 17.81 vs 16.39 years; P = .01) for survival free from cardiovascular death. In the SHEP trial, treatment of isolated systolic hypertension with chlorthalidone stepped-care therapy for 4.5 years was associated with longer life expectancy at 22 years of follow-up.
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    The carriage of CYP2C19*2 and the use of proton-pump inhibitors (PPIs) and calcium-channel blockers (CCBs) has been associated with the diminished efficacy of clopidogrel. However, previous studies have only assessed the isolated impact of these risk factors for clopidogrel poor response. The aim of the present study was to investigate the impact of the combined presence of three risk factors for clopidogrel poor response, that is, the use of CCBs, PPIs and the carriage of CYP2C19*2, on on-treatment platelet reactivity and the occurrence of atherothrombotic events in 725 patients on dual antiplatelet therapy undergoing elective coronary stenting. In a prospective, follow-up study, on-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. The clinical study endpoint was the composite of all-cause mortality, myocardial infarction, stent thrombosis and stroke at 1 year after stenting. Patients with either one or more than one risk factor exhibited increased platelet reactivity (mean relative increase one risk factor: 11% and > 1 risk factor: 22%, respectively). Sixty-four events occurred during follow-up (8.8% of the study population). Patients with one risk factor for clopidogrel poor response did not have an increased risk of the composite endpoint. However, patients using both CCBs and PPIs and carriers of CYP2C19*2 who used CCBs had a statistically significant increased risk of the composite endpoint [hazard ratio(HR)(adj) 2.2 95% CI, 1.0-5.3, P = 0.044 and HR(adj) 3.3 95% CI, 1.1-9.8, P = 0.032, respectively]. The presence of more than one of the three investigated risk factors for clopidogrel poor response is associated with an increased risk of adverse cardiovascular events within 1 year after elective coronary stenting.
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    Proton pump inhibitors have an excellent safety profile and have become one of the most commonly prescribed class of drugs in primary and specialty care. Long-term, sometimes lifetime, use is becoming increasingly common, often without appropriate indications. This paper is a detailed review of the current evidence on this important topic, focusing on the potential adverse effects of long-term proton pump inhibitor use that have generated the greatest concern: B12 deficiency; iron deficiency; hypomagnesemia; increased susceptibility to pneumonia, enteric infections, and fractures; hypergastrinemia and cancer; drug interactions; and birth defects. We explain the pathophysiological mechanisms that may underlie each of these relationships, review the existing evidence, and discuss implications for clinical management. The benefits of proton pump inhibitor use outweigh its risks in most patients. Elderly, malnourished, immune-compromised, chronically ill, and osteoporotic patients theoretically could be at increased risk from long-term therapy.
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    Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).
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    Not all cardiovascular protection provided by statins is explained by their beneficial effects on lipoproteins. Old (e.g., clofibrate) and new (e.g., torcetrapib and ezetimibe) agents, with similar or more intense beneficial effect over lipoproteins, do not reproduce the beneficial effects of statins. Besides their anti-inflammatory and other pleiotropic effects, a blood pressure-lowering effect could be an additional mechanism of cardiovascular protection of statins. Large trials of statins in the primary and secondary prevention of cardiovascular disease did not report an effect on blood pressure, but the use of blood pressure-lowering agents was left to the discretion of physicians during the trial. Post hoc analyses of small trials and a meta-analysis of some of them have suggested that statins could lower systolic blood pressure by approximately 4 mmHg, particularly in patients with high blood pressure. Most studies, however, had small samples and were not blinded. Others had a cross-over or observational design. The overall view of these studies rules out a substantial blood pressure-lowering effect of statins. An effect restricted to subjects with high blood pressure could ultimately derive from the anti-inflammatory effect of statins, since higher levels of C-reactive protein are associated with higher blood pressure. An unequivocal demonstration of an antihypertensive effect of statins, however, is still lacking, and a randomized trial with enough power to evaluate blood pressure variation in a large range of blood pressure values is required to demonstrate whether statins definitely have an antihypertensive effect.
  • Article
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    Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear. To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease. Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease. Tennessee Medicaid program. 20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris. Baseline and follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death). Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization. Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital. In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk. Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.