Disminución de la presión arterial en intervalos de tiempo con los bloqueantes de los canales de calcio dihidropiridínicos
Resumen
Antecedentes
Los bloqueantes de los canales de calcio son una clase heterogénea de fármacos, que incluye los subgrupos dihidropiridínicos y no dihidropiridínicos, comúnmente utilizados en el tratamiento de la hipertensión. No se ha publicado una revisión sistemática del intervalo de 24 horas para el efecto de disminución de la presión arterial.
Objetivos
Evaluar cuánta variación hay en la disminución de la presión arterial sistólica y diastólica por hora con los bloqueantes de los canales de calcio dihidropiridínicos durante un período de 24 horas en pacientes con hipertensión a partir de 18 años de edad, con una presión arterial sistólica inicial de al menos 140 mmHg o una presión arterial diastólica inicial de al menos 90 mmHg, o ambas.
Métodos de búsqueda
Se hicieron búsquedas electrónicas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) (número 1, 2014), MEDLINE (1946 hasta febrero 2014), EMBASE (1974 hasta febrero 2014), y en ClinicalTrials.gov (hasta febrero 2014). También se analizaron las referencias de los estudios publicados y revisiones para identificar ensayos adicionales.
Criterios de selección
Se incluyeron todos los ensayos aleatorios controlados con placebo que evaluaban los efectos por hora de los bloqueantes de los canales de calcio dihidropiridínicos mediante monitorización ambulatoria de la presión arterial en adultos con hipertensión y con un seguimiento de al menos tres semanas.
Obtención y análisis de los datos
Dos autores, de forma independiente, seleccionaron los ensayos incluidos, evaluaron el riesgo de sesgo y analizaron los datos.
Resultados principales
Esta revisión sistemática incluyó 16 ensayos controlados aleatorios de los bloqueantes de los canales de calcio dihidropiridínicos, con 2768 participantes asignados al azar. Los fármacos estudiados incluyeron amlodipino, lercanidipino, manidipino, nifedipino y felodipino (todos administrados una vez al día) y nicardipino (administrado dos veces al día). Los datos se analizaron y se presentaron por hora luego de la dosis. El efecto de disminución de la presión arterial fue estable con el transcurso del tiempo; no hubo diferencias clínicamente importantes en el efecto de disminución de la presión arterial con los bloqueantes de los canales de calcio entre cada hora para la presión arterial sistólica (las diferencias medias por hora calculadas oscilaron entre 9,45 mmHg y 13,2 mmHg) o la presión arterial diastólica (las diferencias medias por hora calculadas oscilaron entre 5,85 mmHg y 8,5 mmHg). Sin embargo, hubo un riesgo moderado de sesgo para este hallazgo. Los bloqueantes de los canales de calcio dihidropiridínicos una vez al día parecieron disminuir la presión arterial en una cantidad relativamente constante a lo largo del intervalo de dosificación de 24 horas.
Conclusiones de los autores
Seis bloqueantes de los canales de calcio dihidropiridínicos estudiados en esta revisión disminuyeron la presión arterial en una cantidad relativamente similar cada hora durante el período de 24 horas. No se conocen los efectos beneficiosos y perjudiciales de este modelo de disminución de la presión arterial. Se necesitan ensayos adicionales con un registro exacto del tiempo de administración de fármacos y con un informe de la desviación estándar de la presión arterial a cada hora. No se intentaron evaluar los efectos adversos de esta revisión debido a la falta de presentación de informes y la corta duración del seguimiento.
PICO
Resumen en términos sencillos
¿El efecto de disminución de la presión arterial de los bloqueantes de los canales de calcio dihidropiridínicos es consistente o variable a través del período de 24 horas?
Antecedentes
La presión arterial alta, también conocida como hipertensión, es un factor de riesgo de eventos cardiovasculares adversos como accidente cerebrovascular y ataque cardíaco. La presión arterial varía mucho en un individuo aunque se han identificado determinados modelos en su ascenso y disminución en la población en general; la presión arterial aumenta a primeras horas de la mañana y disminuye durante la noche. Hay diversas opciones de tratamiento disponibles para el tratamiento de la hipertensión. Los bloqueantes de los canales de calcio dihidropiridínicos son un grupo de fármacos utilizados para disminuir la presión arterial.
Características de los estudios
Esta revisión explora si el efecto de disminución de la presión arterial de los bloqueantes de los canales de calcio dihidropiridínicos en adultos (a partir de 18 años de edad) con hipertensión (presión arterial sistólica [número superior de la lectura de la presión arterial] de al menos 140 mmHg o presión arterial diastólica [número inferior de la lectura de la presión arterial] de al menos 90 mmHg, o ambas) es consistente o variable durante un período de 24 horas. Se realizó una revisión de los estudios que comparaban los efectos de disminución de la presión arterial en 24 horas de seis de estos fármacos versus un tratamiento de control de al menos tres semanas. La presión arterial debía ser medida con un monitor ambulatorio de la presión arterial, que es un dispositivo que mide automáticamente la presión arterial a intervalos regulares. Se realizaron búsquedas de ensayos clínicos hasta febrero de 2014.
Resultados clave
Se encontraron 16 ensayos con 2768 participantes que estudiaban cinco fármacos administrados una vez al día (amlodipino, lercanidipino, manidipino, nifedipino y felodipino) y un fármaco administrado dos veces al día (nicardipino). La cantidad de disminución de la presión arterial con los bloqueantes de los canales de calcio dihidropiridínicos permaneció relativamente igual a cada hora a lo largo de un día de 24 horas. Las diferencias promedio por hora en la presión arterial fueron de entre 9,45 mmHg y 13,2 mmHg para la presión arterial sistólica y de entre 5,85 mmHg y 8,5 mmHg para la presión arterial diastólica. En este momento, no se conocen los efectos beneficiosos y perjudiciales de este modelo de disminución de la presión arterial.
Calidad de la evidencia
La calidad general de las pruebas se consideró moderada. Es probable que los futuros trabajos de investigación tengan una marcada repercusión sobre la confianza en la estimación del efecto y puedan cambiar el cálculo.
Authors' conclusions
Summary of findings
| Dihydropyridine calcium channel blockers compared with placebo for hypertension | |||
| Patient or population: adults with primary hypertension Settings: outpatient Intervention: dihydropyridine calcium channel blockers (CCB) at maximum doses Comparison: placebo | |||
| Outcomes | No of participants | Quality of the evidence | Comments |
| Variation in the decrease in 24‐hour ambulatory hourly systolic blood pressure at 3‐12 weeks | 2768 | ⊕⊕⊕⊝ | A relatively constant blood pressure‐lowering effect at each hour. No subgroup differences demonstrated1 |
| Variation in the decrease in 24‐hour ambulatory hourly diastolic blood pressure at 3‐12 weeks | 2768 | ⊕⊕⊕⊝ | A relatively constant blood pressure‐lowering effect at each hour. No subgroup differences demonstrated1 |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||
| GRADE Working Group grades of evidence | |||
| 1. ANOVA F tests done on each mixed model analysis rarely failed to reject the null hypothesis in tests for heterogeneity. 2. High risk of bias for finding of no difference between hours as Industry‐funded studies were likely designed to show no difference. | |||
Background
Description of the condition
Cardiovascular diseases are widespread and represent the leading cause of death globally (Turnbull 2003). The positive association between increased blood pressure (BP) and the risk of major cardiovascular disease is well established, as are the effects of BP‐lowering drugs to lower these risks in people with moderate to severe elevations in BP (Psaty 2003; Wright 2009).
In the general population, some distinct circadian patterns in BP have been identified. BP declines during sleep, and rises in the early morning hours (Elliott 1999). While the morning spike of BP is associated with an increase in some cardiovascular events (Elliott 1999), disturbances in night‐time patterns (such as blunted drops in BP (non‐dippers) and marked decreases in BP (extreme dippers)) are also associated with increased cardiovascular risks (Kario 2004).
Each of the various classes of drugs used to lower BP act through different modes of action and have been shown to vary in their ability to reduce the risk of various cardiovascular events. For example, thiazide‐type diuretics are more efficacious than calcium channel blockers (CCB) and angiotensin‐converting enzyme inhibitors in preventing heart failure, but are not different in their ability to reduce total cardiovascular events (ALLHAT 2002; Chen 2010).
Potential variability in outcomes not only arises from the class of antihypertensive drugs prescribed but also how BP is measured following treatment. Twenty‐four‐hour monitoring of BP provides more information than clinic measurements as it allows observation of how the BP‐lowering effect of a drug changes over time.
Description of the intervention
CCBs are a heterogeneous class of drugs including dihydropyridines (DHPs), phenylalkylamines, benzothiazepines, and nonselective CCBs. They are used to treat a variety of cardiovascular diseases including hypertension and angina. First‐line treatment with CCBs has been shown to reduce risks of total major cardiovascular events and stroke when compared with a placebo (Turnbull 2003). This review is limited to studying the DHP CCBs. These compounds are more potent vasodilators than drugs in the phenylalkylamine and benzothiazepine subclass (Basile 2004; Sica 2006).
The earliest CCBs were nifedipine (a DHP), diltiazem (a benzothiazepine), and verapamil (a phenylalkylamine). They displayed variability in dose response, had short durations of action, and were associated with numerous adverse effects (Toyo‐Oka 1996). Later, CCBs were developed to decrease negative adverse effects, and increase the duration of action plus decrease the frequency of dosing of the drugs.
How the intervention might work
DHP CCBs prevent the entry of calcium through L‐type calcium channels in the myocardium and vasculature. This reduces contractility of the cardiac muscle, conduction velocities of the sinoatrial and atrioventricular nodes, and causes vasodilation of the vascular smooth muscle (Elliott 2011). DHPs preferentially bind the L‐type calcium channels in the vasculature rather than those of the cardiac muscle (Basile 2004). This general mechanism of action is shared between all DHP CCBs; however, there are pharmacokinetic differences within this subclass. For example, half‐lives of CCBs vary from relatively short (0.2 to 1 hour for nifedipine) to long (44 hours or greater for amlodipine) (Elliott 2011). This suggests possible differences in the time course of effects depending on the drug used.
Why it is important to do this review
A systematic review of the time course of DHP CCBs has not been done. The information from this review will tell us whether there are differences in the time course of BP‐lowering among different drugs within this class. It will also provide valuable information about this class of drugs that can be compared with similar reviews of other classes of drugs (Sekhon 2008). It is possible that different mortality and morbidity effects of BP‐lowering drugs can be explained by differences in the time course of BP lowering.
Objectives
To assess how much variation there is in hourly systolic and diastolic BP lowering by DHP CCBs over a 24‐hour period in people with hypertension aged 18 years or over, with baseline systolic blood pressure (SBP) of at least 140 mmHg or diastolic blood pressure (DBP) of at least 90 mmHg, or both.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs) with random allocation to a standard dose* of a DHP CCB and to a parallel placebo group.
In addition, they had to meet the following criteria:
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duration of follow‐up of at least three weeks;
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BP measured using 24‐hour ambulatory blood pressure monitoring (ABPM) at one or more time points after week three.
*Standard doses defined as any dose within the dose range recommended by the manufacturer for the treatment of hypertension.
Types of participants
People with primary hypertension who were aged over 18 years. Participants had to have a baseline SBP of at least 140 mmHg or DBP of at least 90 mmHg, or both.
We assumed that age does not impact the temporal BP‐lowering effect of this class of drugs.
Types of interventions
Intervention: CCBs of the DHP type including: amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, darodipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, niguldipine, nilvadipine, nimodipine, nisoldipine, and nitrendipine. When more than one dose was studied in a single RCT, we used the highest dose within the recommended dose range to increase the chance of finding a difference in effect at different times.
Control: placebo.
Types of outcome measures
Primary outcomes
Endpoint hourly BP using a 24‐hour ABPM.
Search methods for identification of studies
We searched the Database of Abstracts of Reviews of Effectiveness (DARE) and The Cochrane Database of Systematic Reviews for related reviews.
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2014), Ovid MEDLINE (1946 to February 2014), Ovid EMBASE (1974 to February 2014), and ClinicalTrials.gov (ClinicalTrials.gov) (to February 2014) for RCTs.
We used the Cochrane Highly Sensitive Search Strategy for identifying RCTs in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision) with selected MeSH terms and free‐text terms relating to CCBs and hypertension. We applied no language restrictions. We adapted the MEDLINE search strategy (Appendix 1) into strategies for CENTRAL (Appendix 2), EMBASE (Appendix 3), and ClincialTrials.gov (Appendix 4) using the appropriate controlled vocabulary as applicable.
Searching other resources
We handsearched reference lists of all papers and relevant reviews identified and ISI Web of Science for papers that cite studies included in the review. We contacted authors of relevant papers regarding any further published or unpublished work and authors of trials reporting incomplete information to request the missing information.
Data collection and analysis
Selection of studies
We selected studies primarily based on abstracts and titles, and rejected studies that did not meet the inclusion criteria or that fulfilled the exclusion criteria. For those studies selected, we reviewed the full texts for their overall applicability based on the inclusion criteria. We also examined the reference list of the full‐text papers for their relevance. Two review authors independently assessed the selected studies for inclusion.
Data extraction and management
We entered data into a data extraction form and two review authors independently cross‐checked entries. A second review author double checked all interpolations and calculations. We contacted the investigators of the specific trials to request any missing data.
Assessment of risk of bias in included studies
We assessed the risk of bias following the methodology described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), under the subheadings: sequence generation, allocation sequence concealment, blinding of participants, incomplete outcome data, selective outcome reporting, and other biases.
Measures of treatment effect
The treatment effect was the mean change in systolic and DBP in mmHg (a continuous variable) for each hour over a 24‐hour period. For example, if a trial used 24‐hour ABPM at different points in time between week three and 12, we used the mean of all the measurements.
Unit of analysis issues
We developed the approach to assessing statistical heterogeneity in order to avoid unit of analysis errors.
Dealing with missing data
We attempted to contact the authors of selected articles via email or telephone to request missing data and noted any replies.
Standard deviation data at endpoints are often not included in published reports or are of an unrealistic magnitude. In the event that this was the case and the information could not be obtained from the authors, we imputed standard deviations according to the following hierarchy.
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Standard deviation of the change in endpoint BP obtained from the same trial.
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Weighted mean standard deviation of BP at endpoint calculated from at least three other trials using the same drug and dose regimen.
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Weighted mean standard deviation of BP at endpoint calculated from other trials using the same drug.
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Weighted mean standard deviation of BP at endpoint calculated from all other trials (any drug and dose).
Assessment of heterogeneity
We could not use the Review Manager software's built‐in test for heterogeneity of treatment effect to test for differences in BP‐lowering effect at different hours because of correlated errors introduced by repeated observations on the same participants. Instead, we analyzed the 307 observations in the SBP analysis and the 356 observations in the DBP analysis using linear regression models that compensated for the correlated observations. We performed the linear regressions 1000 times each for the SBP and DBP data. We needed an iterative process because estimating only one SBP or DBP linear model with the reported mean difference (MD) for each hour and study combination would have ignored the variation around each observation (i.e. the variation around the MD for study i in hour j). A single iteration of the process involved generating 307 SBP values (356 for the DBP dataset) randomly selected from normal distributions defined by the reported MD and respective 95% confidence interval (CI). The generated values were then inputted into a linear regression to obtain an estimated total MD across all studies and hours. We repeated this process 1000 times to obtain a distribution of total MDs. We used the Kernel density estimation to identify a normal density function for the 1000 values, and then extracted the mean, upper 95% CI, and lower 95% CI from the density. These analyses were completed using PROC MIXED and PROC KDE in SAS versions 9.4 (SAS Institute Inc., Cary, NC). To account for correlated observations, we assumed variance‐covariance matrices in each linear regression to be heterogeneous compound symmetric. We used the generated values from each iteration to conduct analyses of variance (ANOVA). We computed F‐tests for each iteration. We assumed that observations across hours were likely to be homogeneous if the F‐tests rarely exceeded the critical F values of 1.564 (SBP) or 1.559 (DBP).
Assessment of reporting biases
We assessed publication bias using funnel plots, as outlined in Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2011).
Data synthesis
We entered the mean change from control or baseline plus the standard deviation for each trial and for each hour.
Subgroup analysis and investigation of heterogeneity
We performed a subgroup analysis of individual DHP CCBs or of once‐daily or twice‐daily dosing if possible.
Sensitivity analysis
We planned sensitivity analyses according to participant characteristics, gender, or baseline BP.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
We identified 20 potentially eligible studies, from which we excluded four after screening the full texts. Reasons for exclusion included: smoothed data points causing inaccurate hourly data extraction (Carr 1992; Zachariah 1990), lack of placebo data provided (Viskoper 1991), and too long a time range between data points to accurately assess hourly effects (Honorato 1989).
We reviewed 16 RCTs with 2768 randomized participants for inclusion in the review (Asmar 1992; Bellet 1987; Chrysant 2003; Fagan 1993; Fogari 1996; Fogari 1999; Grimm 2002; Kuschnir 1996; Lacourciere 1998; Mroczek 1988; Omboni 1998; Pandita‐Gunawardena 1999; Toal 1997; van Ree 1996; White 2010; Zanchetti 1993). This total value varied at some hours as some studies provided bi‐hourly data (Asmar 1992), had missing data points for certain hours (Fagan 1993), provided less than 24 hours of data (Bellet 1987), or only provided diastolic data (Kuschnir 1996; Pandita‐Gunawardena 1999).
All study participants had hypertension. Each trial began with a two‐ to four‐week washout of previous antihypertensive medication or placebo run‐in. The criteria for entry differed between the trials and are documented in the Characteristics of included studies table.
All but one of the 16 RCTs explicitly stated both male and female participants were recruited (Zanchetti 1993). However, no RCT reported hourly BP results separately in men and women. Requirements for age varied among the studies and are documented in the Characteristics of included studies table.
This review includes investigations of six different DHPs. Seven of the RCTs studied amlodipine (Chrysant 2003; Grimm 2002; Kuschnir 1996; Lacourciere 1998; Mroczek 1988; Pandita‐Gunawardena 1999; White 2010). Two RCTs studied nicardipine in a twice‐daily regimen, but in different formulations: slow release (SR) (Fagan 1993) and long‐acting (LA) (Bellet 1987). The remaining study drugs were: lercanidipine (Omboni 1998), manidipine (Fogari 1996; Fogari 1999), nifedipine gastrointestinal therapeutic system (GITS) (Toal 1997; Zanchetti 1993), felodipine extended release (ER) (van Ree 1996), and nitrendipine (Asmar 1992). We only included trials that did not allow the use of supplemental antihypertensive agents other than study drugs.
Titrated doses were used in four RCTs (Grimm 2002; Lacourciere 1998; Pandita‐Gunawardena 1999; White 2010). Multiple doses were used in five RCTs (Fagan 1993; Fogari 1996; Omboni 1998; van Ree 1996; White 2010), and, in these RCTs, we used the data points from the highest dose. Five studies did not provide the time of drug administration (Fogari 1996; Fogari 1999; Mroczek 1988; Pandita‐Gunawardena 1999; Zanchetti 1993); in these studies, we chose 8 a.m. as the most likely time of drug administration. Five trials provided standard deviation or standard error (Asmar 1992; Fogari 1996; Toal 1997; van Ree 1996; Zanchetti 1993); however, we deemed the values provided in two of these studies to be too low to be realistic values (Asmar 1992; van Ree 1996). We used imputed standard deviations in these studies, and the remaining stud from Perez 2009. We imputed the standard deviations as 17 mmHg for SBP and 13 mmHg for DBP. These values were the mean standard deviations that were calculated from hourly individual participant data.
The mean duration of follow‐up of the included trials was about seven weeks, and ranged from three weeks (Bellet 1987) to 20 weeks (Grimm 2002). Due to the short duration of these trials, we did not attempt to quantify adverse effects of the study drugs in this review.
Results of the search
Figure 1 summarizes the PRISMA flow diagram for the screening process.
Study flow diagram.
Included studies
See Included studies; Characteristics of included studies table.
Excluded studies
See Excluded studies; Characteristics of excluded studies table.
Risk of bias in included studies
The risk of bias judgments and reasons can be found in Risk of bias in included studies.
Allocation
All of the included trials stated that they were randomized; however, only two of the trials, in which we were able to contact the lead author and received a response, provided information on how randomization took place (Chrysant 2003; Toal 1997). We deemed these two trials to have a low risk of random sequence generation bias. We judged two trials to have high risk of random sequence generation bias (Fagan 1993; White 2010). In these studies, subgroups of the originally randomized participant population were used for ABPM substudies, with no description of how the subgroup populations were selected. The remaining trials did not address how randomization took place and we assessed them as having an unclear risk of selection bias for randomization (Asmar 1992; Bellet 1987; Chrysant 2003; Fogari 1996; Fogari 1999; Grimm 2002; Kuschnir 1996; Lacourciere 1998; Mroczek 1988; Omboni 1998; Pandita‐Gunawardena 1999; van Ree 1996; Zanchetti 1993).
Only two trials provided information on allocation concealment (Chrysant 2003; Toal 1997). We judged these as having a low risk of bias for this field. The remaining trials did not describe methods of allocation concealment and we deemed them to have an unclear risk of bias.
Blinding
All of the 16 trials declared that their studies were double blinded. Only two studies provided information on methods of double blinding, and we deemed them to be at low risk for both performance and detection bias (Chrysant 2003; Toal 1997). Two trials described methods of blinding participants to treatment, but not blinding of personnel or outcome assessment (Bellet 1987; Fogari 1996). We assessed these as having unclear risk of performance and detection bias, as with the remaining studies.
Incomplete outcome data
We assessed eight of the trials as high risk of attrition bias. In six of these trials, we included only ABPM data that were deemed valid by that trial in the analysis (Chrysant 2003; Fogari 1999; Omboni 1998; Toal 1997; White 2010; Zanchetti 1993). The two remaining high‐risk trials did not have balanced numbers or reasons for withdrawals between groups (Lacourciere 1998; Pandita‐Gunawardena 1999).
Selective reporting
We judged all trials to have a low risk of selective reporting bias.
Other potential sources of bias
Twelve of the 16 trials were funded by or involved a pharmaceutical company and we deemed this as a high risk of other potential bias (Bellet 1987; Chrysant 2003; Grimm 2002; Kuschnir 1996; Lacourciere 1998; Mroczek 1988; Omboni 1998; Pandita‐Gunawardena 1999; Toal 1997; van Ree 1996; White 2010).
Figure 2 and Figure 3 provide a summary of the overall risk of bias and, since there is a paucity of low risk of bias, we judged the review to have a moderate to high risk of bias. That is certainly the case for the magnitude of BP lowering shown here and possibly also for the main finding of a no clinically important variation in BP lowering over the 24‐hour period.
Effects of interventions
At each hour throughout the 24‐hour dosing interval, DHP CCBs significantly lowered BP more than placebo (P value < 0.00001 for both SBP and DBP). Estimated mean hourly differences ranged between 9.45 mmHg and 13.2 mmHg for SBP (Analysis 1.1) and ranged between 5.85 mmHg and 8.5 mmHg for DBP (Analysis 1.2). For both the hourly SBP and hourly DBP, the mean BP‐lowering effect remained relatively constant over time with no evidence of any pattern. In order to test whether there were any differences between BP‐lowering effects at the different hours, we estimated the total meta‐analytic effect of BP change across 24 hours from linear regression models (repeated 1000 times each for SBP and DBP). We performed ANOVA F tests on each mixed model analysis, which rarely failed to reject the null hypothesis in tests for heterogeneity (F < Critical F = 1.564 on all but seven of 1000 SBP iterations; F < Critical F = 1.559 on all but one of 1000 DBP iterations).
For most hours, there was no significant heterogeneity. The only exceptions were hours one, two, three, and 11 from the SBP data (where I2 ≥ 50%). We judged these infrequent occurrences to be most likely due to chance, as it was unlikely that there were sources of clinical or methodologic heterogeneity in this review. Because heterogeneity was found in only 16.6% of subgroups in SBP data, we deemed the fixed‐effect model to be most appropriate for analysis of both sets of data.
Adverse effects were inconsistently reported in these trials and, since the trials were short and this was not one of the objectives of this review, we did not attempt to quantify them.
Discussion
Summary of main results
We included 16 RCTs in this systematic review, with 2768 randomized participants. We analyzed data by hourly subgroups and found no significant differences in the BP‐lowering effects of DHP CCBs between each hour, over the course of 24 hours. This result was found for both SBP and DBP. This suggests that the DHP CCBs studied in this review lowered BP by a consistent magnitude throughout the 24‐hour dosing interval. This finding was the same if the seven RCTs studying amlodipine were analyzed alone and was the same when the other once‐daily RCTs analyzing nifedipine, manidipine, felodipine, and lercanidine were analyzed together. We have not calculated the overall BP‐lowering effect, as we were only interested in the variation of BP‐lowering over the 24‐hour period. The magnitude of BP lowering is not meaningful in this review as the included studies used different doses and approaches, for example dose titration. In addition, the BP‐lowering magnitude observed represents an exaggeration of the mean effect, as we specifically selected the highest dose in trials where several doses were studied and there is a high risk of bias for industry‐funded trials such as these.
It is not known at the present time whether the pattern of BP lowering (consistent over the 24‐hour period) is desirable or not. BP normally is reduced significantly during sleep as compared with during the day. It is not known whether further lowering of BP during sleep is desirable or not. It will be important to compare drug and drug class effectiveness in reducing mortality and morbidity with the pattern of BP lowering. Therefore, it is important to do systematic reviews studying the BP‐lowering profile of all drugs and classes of drugs that have been studied in long‐term mortality and morbidity outcome trials (Wright 2009).
Fourteen of the 16 trials used a once‐daily regimen. The remaining two trials studied twice‐daily nicardipine (Bellet 1987; Fagan 1993). When these two nicardipine trials were removed from the analysis, the conclusions of the review were unchanged. One trial of nitrendipine showed a loss of BP‐lowering effect during the second 12 hours after a once‐daily dose (Asmar 1992). When this trial was removed from the analysis it also had no effect on overall BP‐lowering profile or the on the conclusions of the review.
Overall completeness and applicability of evidence
The review authors originally planned to assess the time‐course profile of all CCBs, and include not only RCTs, but cross‐over, and baseline‐controlled trials as well. The first set of searches reflected these goals. However, due to the large amount of relevant trials that were found from the searches, it was deemed that the objectives could be obtained by limiting criteria to the most rigorous trial design, that is, randomized, placebo‐controlled double‐blind trials. In addition, we decided to focus the review on the largest subclass of CCBs, that is, DHPs. One limitation of the review is that we only included studies published in English.
Standard deviations were only reported accurately in three of the 16 included trials. BP variability (standard deviation) is constant in human populations and effect size is relatively insensitive to standard deviation. Therefore, we used imputed standard deviations in the 13 remaining studies using data from Perez 2009. The values provided in this study are from individual participant data, which we believe to be more accurate than pooled values, and are relatively more conservative than any of the values provided in the included studies. This represents a limitation but is unlikely to introduce a potential bias.
Most of the DHP CCBs included in this review were developed to have an antihypertensive effect over a 24‐hour period (Toyo‐Oka 1996). The results of this systematic review demonstrate that the five DHP CCBs (amlodipine, lercanidipine, mandipine, nifedipine, and felodipine) control BP by a relatively constant amount throughout a 24‐hour dosing interval. The evidence is strongest for amlodipine with seven RCTs, intermediate for nifedipine and manidipine with two RCTs each, and weakest for felodipine and lercanidipine with one RCT each.
Quality of the evidence
All included studies stated that they were randomized trials; however, most studies did not address how treatment randomization occurred or how allocation of treatment was concealed, and, therefore, had an unclear risk of selection bias. All included studies also stated that they were double‐blinded trials, but again, most did not describe how double blinding was ensured throughout the trial. Since BP was measured by a computer‐generated program, the chance of loss of blinding having an effect on the BP values was reduced. We assess most of the studies as having an unclear risk of performance and detection bias. We found high risk of attrition bias in eight of the 16 trials, mainly because of the inclusion of study‐defined "valid" ABPM data and exclusion of the remainder. All of the studies had a low risk for reporting bias. Other biases, in the form of pharmaceutical company funding or sponsoring, were found in 12 of the 16 included studies. It is possible that these studies were deliberately designed to show a constant BP‐lowering effect over a 24‐hour period so for this category we judged there to be a high risk of bias. We judged the overall risk of bias to be moderate to high. We have judged it to be high for the magnitude of BP lowering so this review should not be used to estimate the BP‐lowering effect of DHP CCBs. We judged the risk of bias for the main conclusion, no clinically important variation between the 24 different hourly measurements, to be moderate.
Potential biases in the review process
A potential limitation of this review is that due to time constrictions of the review authors, we included only studies written in English. Another limitation is that the time of drug administration was not reported or provided following attempted communication in four of the 16 trials. As a result, time of dosing for 'hour 0' in these trials was estimated as 8 a.m. Funnel plots of the SBP and DBP data did not suggest asymmetry, but there were not enough trials for the funnel plot to provide a good measure of the likelihood of publication bias.
Agreements and disagreements with other studies or reviews
We believe this is the first review of its kind.
Study flow diagram.
Comparison 1 Calcium channel blockeres (CCB) versus placebo, Outcome 1 Systolic blood pressure (BP).
Comparison 1 Calcium channel blockeres (CCB) versus placebo, Outcome 2 Diastolic BP.
| Dihydropyridine calcium channel blockers compared with placebo for hypertension | |||
| Patient or population: adults with primary hypertension Settings: outpatient Intervention: dihydropyridine calcium channel blockers (CCB) at maximum doses Comparison: placebo | |||
| Outcomes | No of participants | Quality of the evidence | Comments |
| Variation in the decrease in 24‐hour ambulatory hourly systolic blood pressure at 3‐12 weeks | 2768 | ⊕⊕⊕⊝ | A relatively constant blood pressure‐lowering effect at each hour. No subgroup differences demonstrated1 |
| Variation in the decrease in 24‐hour ambulatory hourly diastolic blood pressure at 3‐12 weeks | 2768 | ⊕⊕⊕⊝ | A relatively constant blood pressure‐lowering effect at each hour. No subgroup differences demonstrated1 |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||
| GRADE Working Group grades of evidence | |||
| 1. ANOVA F tests done on each mixed model analysis rarely failed to reject the null hypothesis in tests for heterogeneity. 2. High risk of bias for finding of no difference between hours as Industry‐funded studies were likely designed to show no difference. | |||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Systolic blood pressure (BP) Show forest plot | 14 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1 BP hour 0 | 13 | 872 | Mean Difference (IV, Fixed, 95% CI) | ‐11.35 [‐13.64, ‐9.07] |
| 1.2 BP hour 1 | 12 | 855 | Mean Difference (IV, Fixed, 95% CI) | ‐12.53 [‐14.79, ‐10.27] |
| 1.3 BP hour 2 | 14 | 908 | Mean Difference (IV, Fixed, 95% CI) | ‐13.24 [‐15.40, ‐11.09] |
| 1.4 BP hour 3 | 13 | 891 | Mean Difference (IV, Fixed, 95% CI) | ‐11.53 [‐13.73, ‐9.32] |
| 1.5 BP hour 4 | 14 | 908 | Mean Difference (IV, Fixed, 95% CI) | ‐12.59 [‐14.78, ‐10.39] |
| 1.6 BP hour 5 | 13 | 891 | Mean Difference (IV, Fixed, 95% CI) | ‐12.58 [‐14.70, ‐10.46] |
| 1.7 BP hour 6 | 14 | 908 | Mean Difference (IV, Fixed, 95% CI) | ‐11.02 [‐13.19, ‐8.85] |
| 1.8 BP hour 7 | 13 | 891 | Mean Difference (IV, Fixed, 95% CI) | ‐10.84 [‐13.14, ‐8.54] |
| 1.9 BP hour 8 | 14 | 908 | Mean Difference (IV, Fixed, 95% CI) | ‐11.88 [‐14.15, ‐9.61] |
| 1.10 BP hour 9 | 13 | 891 | Mean Difference (IV, Fixed, 95% CI) | ‐13.89 [‐16.16, ‐11.63] |
| 1.11 BP hour 10 | 13 | 868 | Mean Difference (IV, Fixed, 95% CI) | ‐12.07 [‐14.31, ‐9.82] |
| 1.12 BP hour 11 | 13 | 891 | Mean Difference (IV, Fixed, 95% CI) | ‐13.76 [‐15.87, ‐11.66] |
| 1.13 BP hour 12 | 12 | 832 | Mean Difference (IV, Fixed, 95% CI) | ‐12.65 [‐14.80, ‐10.50] |
| 1.14 BP hour 13 | 11 | 815 | Mean Difference (IV, Fixed, 95% CI) | ‐12.91 [‐15.13, ‐10.70] |
| 1.15 BP hour 14 | 13 | 868 | Mean Difference (IV, Fixed, 95% CI) | ‐12.53 [‐14.62, ‐10.44] |
| 1.16 BP hour 15 | 12 | 851 | Mean Difference (IV, Fixed, 95% CI) | ‐10.19 [‐12.50, ‐7.88] |
| 1.17 BP hour 16 | 13 | 868 | Mean Difference (IV, Fixed, 95% CI) | ‐9.45 [‐11.78, ‐7.12] |
| 1.18 BP hour 17 | 12 | 851 | Mean Difference (IV, Fixed, 95% CI) | ‐11.24 [‐13.62, ‐8.86] |
| 1.19 BP hour 18 | 13 | 868 | Mean Difference (IV, Fixed, 95% CI) | ‐10.10 [‐12.46, ‐7.75] |
| 1.20 BP hour 19 | 12 | 851 | Mean Difference (IV, Fixed, 95% CI) | ‐11.13 [‐13.49, ‐8.76] |
| 1.21 BP hour 20 | 13 | 868 | Mean Difference (IV, Fixed, 95% CI) | ‐11.95 [‐14.18, ‐9.71] |
| 1.22 BP hour 21 | 12 | 851 | Mean Difference (IV, Fixed, 95% CI) | ‐11.83 [‐14.20, ‐9.47] |
| 1.23 BP hour 22 | 13 | 868 | Mean Difference (IV, Fixed, 95% CI) | ‐11.18 [‐13.48, ‐8.89] |
| 1.24 BP hour 23 | 12 | 851 | Mean Difference (IV, Fixed, 95% CI) | ‐12.73 [‐15.08, ‐10.38] |
| 2 Diastolic BP Show forest plot | 16 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1 BP hour 0 | 15 | 1022 | Mean Difference (IV, Fixed, 95% CI) | ‐7.79 [‐9.45, ‐6.12] |
| 2.2 BP hour 1 | 14 | 1011 | Mean Difference (IV, Fixed, 95% CI) | ‐8.36 [‐9.99, ‐6.73] |
| 2.3 BP hour 2 | 16 | 1058 | Mean Difference (IV, Fixed, 95% CI) | ‐7.81 [‐9.41, ‐6.22] |
| 2.4 BP hour 3 | 15 | 1041 | Mean Difference (IV, Fixed, 95% CI) | ‐6.14 [‐7.76, ‐4.53] |
| 2.5 BP hour 4 | 16 | 1058 | Mean Difference (IV, Fixed, 95% CI) | ‐7.46 [‐8.98, ‐5.95] |
| 2.6 BP hour 5 | 15 | 1041 | Mean Difference (IV, Fixed, 95% CI) | ‐7.91 [‐9.53, ‐6.28] |
| 2.7 BP hour 6 | 16 | 1058 | Mean Difference (IV, Fixed, 95% CI) | ‐6.44 [‐7.89, ‐4.98] |
| 2.8 BP hour 7 | 15 | 1041 | Mean Difference (IV, Fixed, 95% CI) | ‐6.45 [‐8.04, ‐4.86] |
| 2.9 BP hour 8 | 16 | 1058 | Mean Difference (IV, Fixed, 95% CI) | ‐7.11 [‐8.70, ‐5.52] |
| 2.10 BP hour 9 | 15 | 1041 | Mean Difference (IV, Fixed, 95% CI) | ‐6.53 [‐8.17, ‐4.89] |
| 2.11 BP hour 10 | 16 | 1058 | Mean Difference (IV, Fixed, 95% CI) | ‐5.46 [‐6.98, ‐3.94] |
| 2.12 BP hour 11 | 15 | 1041 | Mean Difference (IV, Fixed, 95% CI) | ‐7.17 [‐8.71, ‐5.64] |
| 2.13 BP hour 12 | 14 | 982 | Mean Difference (IV, Fixed, 95% CI) | ‐6.70 [‐8.39, ‐5.01] |
| 2.14 BP hour 13 | 13 | 965 | Mean Difference (IV, Fixed, 95% CI) | ‐7.02 [‐8.61, ‐5.43] |
| 2.15 BP hour 14 | 15 | 1018 | Mean Difference (IV, Fixed, 95% CI) | ‐6.72 [‐8.30, ‐5.14] |
| 2.16 BP hour 15 | 14 | 1001 | Mean Difference (IV, Fixed, 95% CI) | ‐5.94 [‐7.61, ‐4.28] |
| 2.17 BP hour 16 | 15 | 1091 | Mean Difference (IV, Fixed, 95% CI) | ‐5.85 [‐7.39, ‐4.32] |
| 2.18 BP hour 17 | 14 | 1001 | Mean Difference (IV, Fixed, 95% CI) | ‐8.50 [‐9.58, ‐7.42] |
| 2.19 BP hour 18 | 15 | 1018 | Mean Difference (IV, Fixed, 95% CI) | ‐7.12 [‐8.47, ‐5.77] |
| 2.20 BP hour 19 | 14 | 1001 | Mean Difference (IV, Fixed, 95% CI) | ‐7.29 [‐8.93, ‐5.64] |
| 2.21 BP hour 20 | 15 | 1018 | Mean Difference (IV, Fixed, 95% CI) | ‐7.90 [‐9.24, ‐6.56] |
| 2.22 BP hour 21 | 14 | 1001 | Mean Difference (IV, Fixed, 95% CI) | ‐7.13 [‐8.79, ‐5.46] |
| 2.23 BP hour 22 | 15 | 1018 | Mean Difference (IV, Fixed, 95% CI) | ‐6.95 [‐8.63, ‐5.27] |
| 2.24 BP hour 23 | 14 | 1001 | Mean Difference (IV, Fixed, 95% CI) | ‐6.90 [‐8.51, ‐5.28] |
