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Cochrane Database of Systematic Reviews Protocol - Intervention

Ranolazine for stable angina pectoris

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of ranolazine on cardiovascular and non‐cardiovascular mortality in stable angina patients, used either in monotherapy or in combination therapy, and compared to placebo or any other antianginal agent.

Background

Description of the condition

Stable angina pectoris is a chronic medical condition generally regarded as the main symptomatic manifestation of coronary artery disease (CAD) (NICE 2011). It has been estimated that stable angina affects 58% of patients with CAD (Tarkin 2012), with an annual mortality rate ranging between 0.9% and 1.4% (Fox 2006). Apart from its associated risk of cardiovascular death and recurrent myocardial infarction, it has a significant impact on functional capacity and quality of life (Scirica 2009). Mortality is higher among people with angina than people with no history of CAD at baseline (O'Toole 2008). Factors associated with a poorer prognosis include more severe symptoms, male sex, abnormal resting electrocardiogram (ECG) and previous myocardial infarction (O'Toole 2008).

A universal definition for stable angina has not been agreed internationally, but it is usually recognized clinically by its character, its location and its relation to provocative stimuli (NICE 2010). Thus, anginal pain is identified by the following features: (1) constricting discomfort in the front of the chest, or in the neck, shoulders, jaw or arms; (2) precipitated by physical exertion; and (3) relieved by rest or nitrates within about five to 10 minutes, with typical angina being defined by the presence of all of them (NICE 2010). Although its underlying cause is usually macrovascular CAD, it is also microvascular in some patients (ESC 2006). Importantly, other cardiac conditions different from CAD may be responsible for a typical anginal pain, including aortic valve disease and hypertrophic cardiomyopathy (NICE 2010). Macrovascular CAD refers to dysfunction of the coronary arteries and their main branches, as opposed to microvascular CAD in which dysfunction involves the small coronary arterioles (< 500 μm) (Jones 2012).

The diagnosis of stable angina due to CAD can be established based solely on clinical assessment or with the aid of additional diagnostic testing (NICE 2010). The choice of the diagnostic test (invasive or non‐invasive) is guided by the estimated likelihood of CAD (from clinical assessment) and the consideration of coronary revascularization (NICE 2010). Although current NICE guidelines do not recommend exercise ECG for the evaluation of patients with suspected stable angina, it is usually, in practice, the test of choice to identify inducible ischemia in most of those patients (ESC 2006). Furthermore, it is still recommended for patients with intermediate pre‐test probability of CAD according to American (ACC/AHA 2003; ACC/AHA 2012) and European (ESC 2006; SIGN 2007; ESC 2013) guidelines. As mentioned above, some patients with stable angina do not have macrovascular CAD but a microvascular coronary disorder, which can only be suspected with a normal coronary angiography (Di Fiore 2013). Since the evaluation of a patient with stable angina do not always include a coronary angiography, a group of patients with microvascular coronary disorders will remain unidentified with this approach.

Description of the intervention

The management of stable angina includes lifestyle modifications, pharmacological therapy and revascularization interventions. Treatment is aimed at improving prognosis (by preventing myocardial infarction and death) and minimizing or abolishing symptoms. All of the above mentioned management modalities have the potential to meet both treatment aims (ESC 2006). However, regarding pharmacological management, the main aim of anti‐anginal drug treatment is to prevent episodes of angina and the main aim of secondary prevention treatment is to prevent cardiovascular events such as heart attack and stroke (NICE 2011). Anti‐anginal drugs can be classified as first‐line (adrenergic beta antagonists, calcium channel blockers) or second‐line (long‐acting nitrates, ivabradine, nicorandil, ranolazine, trimetazidine) (Tarkin 2012). Anti‐anginal treatment is recommended to start in monotherapy with one of the first‐line drugs. If symptoms are not satisfactorily controlled, a combination of two first‐line drugs is recommended. Second‐line drugs are recommended as add‐on therapy when a combination of two first‐line drugs cannot be accomplished, or as monotherapy when none of the first‐line drugs can be used (NICE 2011; ESC 2013). Adding a third anti‐anginal drug can be considered only when revascularization is not an option or as a temporary measure while patient awaits for revascularization (NICE 2011). However, since ranolazine is the only second‐line drug approved by the U.S. Food and Drug Administration (FDA) (Hawwa 2013), American guidelines (ACC/AHA 2012) only recommend the use of ranolazine in a roughly similar way to second‐line drugs in European guidelines.

Ranolazine was approved by the U.S. FDA in 2007 for use in a maximum dose (extended release) of 1000 mg twice daily (FDA 2007), and by the European Medicines Agency (EMA) in 2008 for use in a maximum dose (prolonged‐release) of 750 mg twice daily (EMA 2008). The immediate release presentation shows peak plasma concentrations within one hour, with an estimated half‐life of seven hours (Jerling 2006). The ranolazine extended‐release preparation reduces the frequency of angina episodes, improves exercise performance and delays the development of exercise induced angina and ST‐segment depression (ACC/AHA 2012). Although these effects are considered to be dose‐related (Chaitman 2011), they have been observed to be modest (EMA 2008) and of uncertain clinical significance (NICE 2011). Furthermore, there is no evidence on the effects of ranolazine on long‐term outcome in patients with stable angina, as well as on the addition of ranolazine to a calcium channel blocker (NICE 2011). On the other hand, an advantage of ranolazine is that it does not cause significant haemodynamic changes, with an average of < two beats per minute reduction in heart rate and < 3 mmHg decrease in systolic blood pressure (ACC/AHA 2012). However, it is associated with a dose‐dependant increase in QT‐interval, with a mean increase of 6 ms at maximal recommended dosing (ACC/AHA 2012). More recently, an anti‐arrhythmic (antifibrillatory) effect of ranolazine has been proposed, but current evidence is based only on small non‐controlled trials (Hawwa 2013). Contraindications to ranolazine are prolonged QT‐interval and coadministration with other QT‐prolonging drugs, previous history of ventricular tachycardia and moderate to severe renal impairment or severe hepatic failure (Tarkin 2012). The most common adverse events related to the use of ranolazine are headache (5.5%), dizziness (1 to 6%), constipation (5%) and nausea (≤ 4%; dose related). Although there is concern about QT prolongation on ECG, its actual prevalence has been estimated to be < 1% (Ranexa 2013).

How the intervention might work

Early studies on the effects of ranolazine in stable angina patients have been performed using its immediate release formulation. However, given that its action was deemed significant only in the peak measurements, an extended release formulation was developed, which was finally approved for use in stable angina patients (Keating 2008).

Overall, ranolazine has been shown to improve exercise tolerance test (ETT) parameters and angina frequency in stable angina patients without any substantial haemodynamic effect (Savarese 2013). However, it has also been related to prolongation of the QTc interval, although not pro‐arrhythmic at therapeutic doses (Thadani 2012). Moreover, it has rather been shown to have anti‐arrhythmic effects by reducing atrial and ventricular arrhythmias (Hawwa 2013).

A number of subgroup analyses have been performed for ranolazine in stable angina patients. The effects of ranolazine on ETT parameters have been found to be greater among women, compared with men. However, its effects on decrease in angina frequency and nitroglycerin consumption were comparable among those groups (Wenger 2007). Differences among age groups have also been evaluated. Although efficacy is similar among patients aged 70 or older and patients younger than 70, its safety profile was better in the younger group (Rich 2007). Finally, differences among diabetic and non‐diabetic patients have also been sought. Although ranolazine has not been found to have a different effect in diabetic patients regarding ETT parameters, angina frequency and nitroglycerin consumption, it does have been related to a significant reduction in HbA1c levels (Patel 2008).

Why it is important to do this review

Although ranolazine reduces angina episodes and improves ETT parameters, its impact on the long‐term prognosis in stable angina patients remains unclear. Moreover, the clinical significance of those effects is still a matter of debate (NICE 2011). Even though the main indication for ranolazine in stable angina patients is as add‐on therapy, the evidence regarding its use in combination with some first‐line drugs is still lacking (NICE 2011). Besides, more evidence is needed regarding its use in monotherapy, since it might be an option for those patients who cannot use any of the first‐line drugs (NICE 2011; ESC 2013) or even be recommended as a first‐line drug given its apparently better side effects profile compared with classical anti‐anginal agents (ACC/AHA 2012). In view of these gaps in the knowledge of the role of ranolazine in the management of stable angina patients, a systematic analysis of the pertinent high quality up‐to‐date evidence is needed.

Objectives

To assess the effects of ranolazine on cardiovascular and non‐cardiovascular mortality in stable angina patients, used either in monotherapy or in combination therapy, and compared to placebo or any other antianginal agent.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised, controlled, parallel‐group and cross‐over trials, with double blinding (participants and trial personnel), which assess the effects of ranolazine in the management of stable angina pectoris, irrespective of the number of groups and the length of follow‐up. For safety outcomes, however, we will also include trials irrespective of blinding as far as they meet the other above mentioned criteria. We will include studies reported as full‐text, those published as abstract only, and unpublished data.

Types of participants

We will include adult patients (aged 18 or older) with a diagnosis of stable angina pectoris, irrespective of gender, precedence, setting, previous treatment status, co‐morbidities and severity of symptoms. The diagnosis of stable angina pectoris can be established based on clinical history, myocardial ischemia demonstrated by functional tests or significant obstructive CAD demonstrated by angiography. Regarding studies which include only a subset of relevant participants, we will include them if results are separately reported for that group of participants.

Types of interventions

We will include trials comparing ranolazine (given orally for at least one week as either monotherapy or in combination therapy, irrespective of dose, presentation (immediate release or extended release) and daily frequency) with placebo or other antianginal agents. We will include the following co‐interventions provided they are not part of the randomised treatment: other antianginal agents (long‐acting nitrates, adrenergic beta antagonists and/or calcium channel blockers), statins, antiplatelet agents, antihypertensive agents and surgical interventions for CAD. We will include trials under any of the following designs:

Monotherapy

  • Ranolazine versus placebo.

  • Ranolazine versus first‐line anti‐anginal drugs, grouped by class: 1) adrenergic beta antagonists and 2) calcium channel blockers.

  • Ranolazine versus other second‐line anti‐anginal drugs, grouped as follows: 1) long‐acting nitrates, 2) ivabradine, 3) nicorandil and 4) trimetazidine.

Combined therapy

  • Ranolazine combined with first‐line anti‐anginal drugs (grouped by class as mentioned before) versus placebo combined with first‐line anti‐anginal drugs (grouped by class as mentioned before).

  • Ranolazine combined with other second‐line anti‐anginal drugs (grouped as mentioned before) versus placebo combined with other second‐line anti‐anginal drug (grouped as mentioned before).

  • Ranolazine combined with first‐line anti‐anginal drugs (grouped as mentioned before) versus other second‐line anti‐anginal drugs (grouped as mentioned before) combined with first‐line anti‐anginal drugs (grouped as mentioned before).

  • Ranolazine combined with other second‐line anti‐anginal drugs (grouped as mentioned before) versus first‐line anti‐anginal drugs (grouped as mentioned before) combined with other second‐line anti‐anginal drugs (grouped as mentioned before).

Types of outcome measures

We will consider effectiveness and safety outcome measures, and only measures taken at the largest time point within each study. For the outcomes considered, we will include only results measured with a follow‐up of at least six weeks. Of note, we will include studies irrespective of whether or not they assessed the outcomes listed below.

Primary outcomes
Effectiveness

  • Cardiovascular mortality, expressed as a proportion of total study population.

Safety

  • Non‐cardiovascular mortality, expressed as a proportion of total study population.

Secondary outcomes
Effectiveness

  1. All‐cause mortality, expressed as a proportion of total study population.

  2. Quality of life, measured with general scales: Medical Outcomes Study Short Form‐36 (SF‐36), World Health Organization Quality of Life tool (WHOQOL), Illness Perception Questionnaire (IPQ) and Nothinghan Health Profile (NHP) (Silva 2011); or specific scales: Seattle Angina Questionnaire (SAQ), MacNew Heart Disease Health‐Related QoL Questionnaire, Ferrans and Powers QoL Index and Speak from the Heart Chronic Angina Checklist (Young 2013); expressed as mean differences (MDs).

  3. Acute myocardial infarction incidence (fatal and non‐fatal), defined as the proportion of participants who suffer one or more episodes of acute myocardial infarction, expressed separately for fatal acute myocardial infarction (AMI) and non‐fatal AMI.

  4. Need for revascularization procedure, expressed as a proportion of total study population.

  5. Angina episodes frequency, measured as a weekly average, expressed as means difference.

  6. Costs of health care. We will consider any information regarding costs of study interventions and related medical care (hospitalizations, additional interventions and outpatient health care).

Safety

  • Adverse events incidence, defined as the proportion of participants who suffer one or more serious (non‐cardiac life‐threatening) or non‐serious events, expressed as a whole but separately for each category.

Search methods for identification of studies

Electronic searches

We will search the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid) and the Conference Proceedings Citation Index‐Science (CPCI‐S)‐‐1990‐present (Web of Science/Thomson Reuters). We have included a detailed MEDLINE search strategy in Appendix 1. We will adapt search strategies for the other databases from the MEDLINE search strategy. The Cochrane highly sensitive search strategy for identifying randomised trials, sensitivity‐maximizing version will be applied to MEDLINE and adapted for EMBASE and Web of Science (Lefebvre 2011). We will search these databases from date of inception to present and will not apply language restrictions.

Searching other resources

In an effort to identify further ongoing, unpublished and published trials (van Enst 2012) we will search the following resources (Higgins 2011):

  1. National and regional databases (since most of these databases do not have an Advanced Search tool, we will limit the search strategy to the search terms "ranolazine" or "雷诺嗪" as needed):

    1. African Index Medicus (AIM, Africa) (http://indexmedicus.afro.who.int/)

    2. Informit Health Collection (Australasia) (http://www.informit.com.au/health.html)

    3. VIP Information/Chinese Scientific Journals Database (CSJD‐VIP, China) (http://www.cqvip.com/)

    4. Index Medicus for the Eastern Mediterranean Region (IMEMR, Easter Mediterranean) (http://www.emro.who.int/information‐resources/imemr‐database/)

    5. IndMED (India) (http://indmed.nic.in/indmed.html)

    6. KoreaMed (Korea) (http://www.koreamed.org/SearchBasic.php)

    7. LILACS (Latin America and the Caribbean) (http://lilacs.bvsalud.org/es/)

    8. Index Medicus for South‐East Asia Region (IMSEAR, DSpace, South‐East Asia) (http://imsear.hellis.org/)

    9. Western Pacific Region Index Medicus (WPRIM, Western Pacific) (http://www.wprim.org/).

  2. Grey literature databases:

    1. OpenGrey (Europe, formerly OpenSIGLE (Stock 2011)) (http://www.opengrey.eu/)

    2. National Technical Information Service (NTIS, U.S.) (http://www.ntis.gov/).

  3. Prospective trial registers search portals: WHO International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/en/) and MetaRegister of Current Controlled Trials (mRCT) (http://www.controlled‐trials.com/mrct/). Although ClinicalTrials.gov (http://www.clinicaltrials.gov/) is already included within both above‐mentioned trial registers (van Enst 2012), we will undertake a separate search due to additional features in ClinicalTrials.gov.

  4. Conference abstracts:

    1. American Heart Association Scientific Sessions since 2009 until 2014 (http://my.americanheart.org/professional/Sessions/ScientificSessions/Archive/Archive‐Scientific‐Sessions_UCM_316935_SubHomePage.jsp)

    2. European Society of Cardiology Congresses since 2007 until 2014 (http://www.escardio.org/congresses/past_congresses/Pages/Past‐Congresses.aspx).

  5. Other reviews: checking the studies included in other relevant reviews retrieved from searches of

    1. Database of Abstracts of Reviews of Effects (DARE) through the Centre for Reviews and Dissemination (CRD) (http://www.crd.york.ac.uk/CRDWeb/)

    2. NHS Economic Evaluation Database (NHS EED) through the CRD (http://www.crd.york.ac.uk/CRDWeb/)

    3. Health Technology Assessment Database (HTA Database) through the CRD (http://www.crd.york.ac.uk/CRDWeb/).

  6. Approval documents from the U.S. FDA (http://www.fda.gov/) and the EMA (http://www.ema.europa.eu/).

  7. Checking reference lists of included studies and other relevant papers identified through the search process.

  8. The website of Gilead Sciences (http://www.gilead.com/), the company which discovered, developed and commercialised Ranozaline.

Data collection and analysis

Selection of studies

Two review authors (LV, JM) will independently screen titles and abstracts for inclusion of all the potential studies we identify from searches, and will code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. If there are any disagreements, we will ask a third review author (JB) to arbitrate. We will retrieve the full‐text study reports/publication and two review authors (LV, JM) will independently screen the full‐text and identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third review author (JB). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the Cochrane review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table.

Data extraction and management

We will use a data collection form for study characteristics and outcome data which has been piloted on at least one study included in the review. Four review authors (JB, LV, DR, JM) will be involved in both processes so that two review authors independently analyse each included study. We will resolve disagreements by consensus or by involving a third review author (CS). One review author (JB) will transfer data into RevMan 2014. We will double‐check that study characteristics and outcome data are entered correctly by comparing the data presented in the systematic review with the study reports. We will extract the following study characteristics:

  1. Methods: date of study, study design, method of randomisation, method of concealment of allocation, blinding, power calculation, duration of follow‐up, number of patients randomised, exclusions post‐randomisation, withdrawals (and reasons), number of patients analysed (according to type of analysis) and intention‐to‐treat analysis (yes/no, for each outcome).

  2. Participants: N, procedence (countries), setting/location, mean age, age range, gender (male %), severity of condition, diagnostic criteria, co‐morbidities, inclusion and exclusion criteria.

  3. Interventions: intervention (including type of formulation), comparison, concomitant medications, excluded medications and duration of treatment.

  4. Outcomes: primary and secondary outcomes (efficacy and safety) specified and collected, and time points reported. For each outcome: outcome definition, method of measurement and unit of measurement.

  5. Notes: trial funding and notable conflicts of interest of trial authors.

Assessment of risk of bias in included studies

Three review authors (JB, DR, LV) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving a third review author (CL). We will assess the risk of bias according to the following domains:

  1. Random sequence generation (selection bias).

  2. Allocation concealment (selection bias).

  3. Blinding of participants and personnel (performance bias).

  4. Blinding of outcome assessment (detection bias).

  5. Incomplete outcome data (attrition bias).

  6. Selective outcome reporting (reporting bias).

  7. Other bias (e.g. industry funding).

We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will take into account the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) regarding 'Risk of bias' assessment of crossover studies. We will summarise the risk of bias judgements across different studies for each of the domains listed. Where information on risk of bias relates to unpublished data or correspondence with a trial author, we will note this in the 'Risk of bias' table. Regarding selective reporting bias assessment, we will perform an additional handsearch in order to identify published study protocols.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Assessment of bias in conducting the systematic review

We will conduct the Cochrane review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will analyse dichotomous data as odds ratios (ORs) or risk ratios with 95% confidence intervals (CIs) and continuous data as MD with 95% CIs. For quality of life data we will use standardized mean differences (SMD), since it is likely to be measured with different tools. We will enter data presented as a scale with a consistent direction of effect.

We will narratively describe skewed data reported as medians and interquartile ranges.

Unit of analysis issues

We will include randomised controlled trials (RCTs) with either a simple parallel group or a crossover design. A crossover design is suitable for this Cochrane review because stable angina pectoris is a relatively stable chronic manifestation of disease and the interventions we are going to assess have only a temporal effect. We will take into account the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) regarding statistical analysis of crossover studies.

Dealing with missing data

We will contact trial authors or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). Where this is not possible, we will obviate data and perform analyses only with available data. We will explore the impact of obviating or imputing missing data in the overall assessment of results by a sensitivity analysis

Assessment of heterogeneity

We will statistically assess heterogeneity among study results by means of the Chi² test with a P value of 0.10 as cut‐off point. We will further assess heterogeneity by using the I² statistic, considering the following thresholds for interpretation: < 25%: low heterogeneity; ≥ 25% but < 50%: moderate heterogeneity; ≥ 50% but < 75%: high heterogeneity; and ≥ 75% very high heterogeneity (in which case meta‐analyses will not be performed) (Higgins 2003). 

Assessment of reporting biases

We will perform tests for funnel plot asymmetry only for those meta‐analyses in which 10 or more studies are included (Sterne 2011). Where there is no significant heterogeneity, we will use Egger's test (Egger 1997) for meta‐analysis of continuous data expressed as MDs and Harbord's test (Harbord 2006), for dichotomous data expressed as ORs. If there is significant heterogeneity, we will use Rücker's test (Rücker 2008) for meta‐analysis of dichotomous data expressed as ORs. For those meta‐analyses including fewer than 10 studies, we will use only visual inspection of funnel plots (Sterne 2011).

Data synthesis

We will undertake meta‐analyses only where this is meaningful i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense. We will use fixed‐effect meta‐analysis to calculate effect estimates if there is no significant heterogeneity. For results with significant heterogeneity, we will use random‐effects meta‐analysis to calculate effect estimates.

Subgroup analysis and investigation of heterogeneity

We plan to carry out subgroup analyses based on the following variables:

  1. Age.

  2. Gender.

  3. Previous acute myocardial infarction status.

  4. Patients undergoing percutaneous coronary intervention (PCI).

  5. Number of revascularization procedures.

We will use the formal test for subgroup interactions in RevMan 2014. Additionally, if we find both significant heterogeneity and funnel plot asymmetry, we will compare the effect estimates obtained by both random‐effects and fixed‐effect models to determine whether or not the random‐effects estimate is biased by the findings of smaller studies (since this would be expected in such a case) (Sterne 2011).

Sensitivity analysis

We plan to undertake several sensitivity analyses to explore the effects of the decisions we make throughout the review process, including:

  1. Restriction to trials with low risk of bias (those which have at least three domains graded as low risk of bias).

  2. Exchanging the statistical approach for data synthesis (random‐effects vs fixed effects).

  3. Changing the measures of treatment effects for dichotomous and continuous data.

  4. Changing the method of dealing with missing data (ignoring vs imputing with replacement values‐poor outcomes)

  5. Those relevant issues identified during the analyses of studies.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this Cochrane review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline what the remaining uncertainties are in the area.