Effect of early treatment with anti‐hypertensive drugs on short and long‐term health outcomes in patients with an acute cardiovascular event
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary
To determine the effect of early treatment with antihypertensive drugs on short‐term and long‐term health outcomes, in patients with an acute cardiovascular event.
Secondary
To determine the effect of early treatment with anti‐hypertensive drugs on blood pressure and heart rate during the time the drug is being administered to patients with an acute cardiovascular event.
Background
Blood pressure lowering drugs are frequently used in the treatment of patients with an acute cardiovascular event (such as acute myocardial infarction, stroke, acute aortic dissection, etc). However, the effect of these drugs on short and long‐term health outcomes, is presently unknown for most conditions. Antihypertensive therapy has the potential to cause both benefit and harm and no systematic review has been done to try to measure the overall benefits or harms of an early therapy (starting within 24 hours). The rationale of using anti‐hypertensive drugs in the early phase of acute cardiovascular (CV) event is not even clear in some situations. In acute ischemic stroke, for example, elevated blood pressure might be a manifestation in the early phase as an appropriate compensatory mechanism. Lowering the blood pressure in this phase might result in further ischemia due to decreased perfusion [Strandgaard 1976].
There are 4 systematic reviews (SR) dealing with acute myocardial infarction (one SR for each different class of anti‐hypertensive drug; Held 1989 for CCB, Yusuf 1988 for nitrates, Yusuf 1985 for BB, AMICG 1998 for ACEI). There are two SRs dealing with acute stroke (Horn 2004 for CCB, BASC 2001 for different interventions). However, all of these systematic reviews are not up‐to‐date and are either not limited to early treatment (AMICG 1998, Held 1989, Yusuf 1985, Horn 2004, BASC 2001); or included active treatment comparators (Yusuf 1988). The time of starting treatment is a key point in the pharmacological management of any acute clinical setting due to interference with the natural physiological compensatory mechanisms that are activated during the early phase of these acute conditions. The bottom‐line is that in this early phase of an acute cardiovascular event all organs and systems are more susceptible to changes in blood pressure, heart rate and other physiological parameters. Anti‐hypertensive drugs given in this phase alter these normal physiological compensatory mechanisms. The purpose of this systematic review is to determine whether the benefits exceeds the harms when anti‐hypertensive drugs are administrated in this early phase of an acute cardiovascular event compared to placebo or no treatment. However, this systematic review will also be different from all existing SR by studying all acute cardiovascular events in one review. The reason for doing that is to determine to what degree these drugs have common effects across these different acute conditions and to explore to what extent the drugs produce effects that are specific to the condition.
Objectives
Primary
To determine the effect of early treatment with antihypertensive drugs on short‐term and long‐term health outcomes, in patients with an acute cardiovascular event.
Secondary
To determine the effect of early treatment with anti‐hypertensive drugs on blood pressure and heart rate during the time the drug is being administered to patients with an acute cardiovascular event.
Methods
Criteria for considering studies for this review
Types of studies
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Randomized controlled trials (RCTs) with parallel design comparing an anti‐hypertensive drug with placebo or no treatment in patients with acute cardiovascular event.
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RCTs must have a minimum of follow‐up of 24 hours and must provide data for at least one of the primary outcome measures.
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RCTs must required patients to start the anti‐hypertensive treatment within 24 hours of the onset of the acute cardiovascular event.
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RCTs that have an active comparator will be excluded.
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Cross‐over trials will be excluded.
Types of participants
Participants must be started within 24 hours of the onset of any of the following acute cardiovascular events: myocardial infarction, unstable angina, acute left‐ventricular failure with pulmonary oedema, acute aortic dissection, acute renal failure, hypertensive encephalopathy, stroke, intracranial haemorrhage, sub‐arachnoid haemorrhage.
Types of interventions
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Any anti‐hypertensive drug† administered as an early treatment^
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Placebo or no early antihypertensive treatment*
†Anti‐hypertensive drug belonging to any of the following classes of drugs: nitrates (including nitroprusside), beta adrenergic antagonists (BB), angiotensin converting enzyme inhibitors (ACEI), calcium channel blockers (CCB), dopamine agonists, alpha‐adrenergic antagonists, diuretics (furosemide and thiazides), direct vasodilators (diazoxide, hydralazine) and others (reserpine, clonidine, alfa‐methyldopa, trimethaphan).
^Early antihypertensive treatment is defined as any of the above drugs started within 24 hours of the onset of an acute cardiovascular event.
*Placebo is defined as inert substance designed to resemble the drug being tested but has no active ingredient and has no treatment effect. In trials, where a placebo is used as a comparator, all patients in the placebo group usually receive the same medical treatment, except for the drug being tested, as the experimental group. This is due to the utilization of a double‐blind study design in these trials. In trials where a no early antihypertensive treatment is used as a comparator all patients of this group also usually receive the same medical treatment as the experimental group, except that no early antihypertensive treatment is given. In these trials the design is open‐label and not blinded.
Note: Trials comparing an anti‐hypertensive drug versus active comparator (such us an anti‐hypertensive drug, morphine, magnesium, halothane, etc.) will be excluded.
Types of outcome measures
Primary outcomes
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All‐cause mortality
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Non‐fatal serious adverse events: including but not limited to myocardial infarction, stroke, congestive heart failure, life‐threatening arrhythmias, renal failure, major bleeding, or any serious event that is known to cause prolongation of hospitalization
Secondary Outcome
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Total weighted mean change in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR), during the treatment period.
Search methods for identification of studies
Search Strategy:
See: Collaborative Review Group search strategy. We will use wild symbols and letters for this extensive search. For the meaning of these abbreviations, see Collaborative Review Group.
MEDLINE, EMBASE, and Cochrane clinical trial register from Jan 1966 to April 2007 will be searched for randomized controlled trials using an extensive search strategy to identify all relevant articles. We will also browse the reference lists in review articles and trials for any studies that may have not been identified by the search strategy. In case of missing information in the retrieved articles, authors will be contacted.
The search strategy applied to identify all antihypertensive drugs and trials is as follows.
Searched key words: controlled clinical trial, randomized controlled trials, meta‐analysis, myocardial infarction, unstable angina, acute left‐ventricular failure with pulmonary oedema, acute renal failure, hypertensive encephalopathy, stroke, intracranial haemorrhage, sub‐arachnoid haemorrhage.
We also list all antihypertensive drugs:
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nitrates: nitroglycerine, isosorbide, nitroprusside;
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beta antagonists: acebutolol, atenolol, bisoprolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, practolol, propranolol, sotalol, timolol;
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calcium channel blockers: amlodipine, ranidipine, azelnidipine, barnidipine, bencyclane, benidipine, bepridil, cilnidipine, cinnarizin, clentiazem, darodipine, diltiazem, efonidipine, elgodipine, etafenone, fantofarone, felodipine, fendiline, flunarizine, gallopamil, isradipine, lacidipine, lercanidipine, lidoflazine, lomerizine, manidipine, mibefradil, nicardipine, nifedipine, niguldipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline, prenylamine, semotiadil, terodiline, tiapamil, verapamil;
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angiotensin converting enzyme inhibitors: alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, derapril, enalapril, fosinopril, idapril, Imidapril, lisinopril, moexipril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril, zofenopril;
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dopamine agonists: fenoldopam,
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alfa‐adrenergic antagonists: urapidil, ketanserine, phentolamine, prazosin,
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direct vasodilators: diazoxide, hydralazine; others: clonidine, guanethidine, trimethaphan camsylate, reserpine, methyldopa.
Data collection and analysis
Data abstraction:
Two reviewers (MIP & VM) will independently decide whether a trial will be included and will extract the data from the included studies. Discrepancies will be resolved by discussion. Absence of consensus will be resolved by a third reviewer (JMW). Cochrane quality scoring system will be used for concealment of allocation: A (adequate), B (unclear), C (clearly inadequate. Authors will be contacted in case of missing information.
Analyses:
For the analysis of the data, Cochrane review manager software, RevMan 4.2, will be used.
Quantitative analyses of outcomes will be based on intention‐ to‐treat principles as much as possible. We will use weighted mean difference to combine continuous variables and relative and absolute risk difference (with 95% confidence interval) will be calculated for dichotomous outcomes. Pooled risk differences obtained from a DerSimonian‐Laird fixed effect model will be converted to numbers needed to treat (NNTs).
Heterogeneity between trial results will be tested using chi‐squared test, where p less than 0.05 will be taken to indicate significant heterogeneity.
As it is stated in our primary objective the effects of early treatment with antihypertensive drugs on short‐term (day 1 & 10) and long‐term (? 30 days) mortality and morbidity in patients with an acute cardiovascular event will be explored. To quantify the occurrences of outcomes the cumulative incidence reported in each trial (based on full intention to treat principles) for that particular outcome will be used. For example, when trials had a follow‐up equal to or longer than 30 days we will include the cumulative incidence reported in each trial for that outcome from randomization to end of follow‐up to calculate the long‐term effect* (see note below). For our day 10 measure we will include the cumulative incidence from time of randomization to day 10 inclusive (or at discharge from hospital when trial does not report the time ‐ the assumption here is that the average hospitalization is about 7‐10 days). Our day 1 measure will include the cumulative incidence from time of randomization to hour 48 inclusive.
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*Note: In case the experimental antihypertensive treatment has been prolonged further than day 10, the data beyond this day will not be included in the analysis. The assumption here is that survivors beyond this point have effects from the extended or long‐term antihypertensive treatment and it is not possible to differentiate between the effects from the early treatment and the effects from the extended treatment.
When possible, we will also do a further analysis of the incidence of the outcomes for the time 0‐48 hour, 3 to 10 day, and beyond day 29. In order to calculate these, we will count the cumulative incidence of the outcome from time of randomization to hour 48, only those events occurring from day 3 to day 10, and only those events occurring after day 29, respectively.
Data for blood pressure reduction will be combined using a weighted mean difference method, whereby the trials are weighted according to the number of subjects in the trial and the within‐study variance. If some of the trials do not report a within‐study variance for blood pressure change an imputed standard deviation (SD) based on the end point measurement will be used.
Several sensitivity analyses will be performed to test robustness including the use of both fixed and random effect models, 95 and 99 % CI. Sensitivity analysis will also be performed according to the class of drug, and clinical condition. Other exploratory sensitivity analysis will be done for route of administration, dose, timing, and duration of antihypertensive treatment.
