Chronic Angina
Conditions
Brief summary
According to the American Heart Association (AHA) 2011 update of heart disease and stroke statistics, more than 9 million adult patients in the United States (US) have angina. This update also notes that a study of 4 national cross-sectional health examination studies found that, among Americans 40 to 74 years of age, the age-adjusted prevalence of angina was higher among women than men. Per ACC/AHA guidelines, the goal of antianginal therapy is the complete or near complete elimination of anginal chest pain and a return to normal activities and functional capacity. However, evaluating angina and responses to antianginal therapy is often not straightforward. This is particularly true of female patients with angina. Because angina and response to antianginal therapy may differ in men and women, an instrument designed specifically to address symptomatology in women with angina could enhance our understanding and characterization of angina and responses to therapy in this population. The current study will evaluate the validity, reliability, and responsiveness of the newly developed Women's Ischemia Symptom Questionnaire (WISQ) based on changes in angina symptomatology in a female angina population treated with ranolazine, compared with the widely used Seattle Angina Questionnaire (SAQ).
Interventions
DRUGRanolazine
Oral dosage form.
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 3 months of documented history of stable angina or angina equivalents that is relieved by rest and/or sublingual NTG * Taking antianginal therapy with beta-blockers, and/or dihydropyridine calcium antagonists, and/or long-acting nitrates for at least 4 weeks * Mean angina frequency of ≥ 2 attacks per week * Documented clinical evidence of ischemia
Exclusion criteria
* Clinically significant hepatic impairment * Uncontrolled clinically significant cardiac arrhythmias or a history of ventricular fibrillation, torsades de points, or other life-threatening ventricular arrhythmias not associated with acute coronary syndrome * Treatment with strong cytochrome P450 inhibitors including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, or saquinavir * Prior treatment with ranolazine * End-stage renal disease requiring dialysis * Myocardial infarction or unstable angina
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the Validity of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and Nitroglycerin (NTG) Consumption Before and Following Treatment With Ranolazine Assessed as Coefficient of Determination (R^2) | Baseline to Week 4 | Validity of the WISQ was assessed by regression analysis. Results of this analysis are reported as the estimated coefficient of determination (R\^2) of the WISQ Total Score at 4 weeks regressed on 4-week angina frequency, 4-week NTG use, and DASI score at 4 weeks. For mean (SEM) Baseline and Week 4 values for angina frequency and NTG use, please refer to Secondary Outcome Measures 7 and 8. For mean (SEM) Baseline and Week 4 DASI values, please refer to Secondary Outcome Measure 9. |
| Evaluate the Reliability of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and NTG Consumption Before and Following Treatment With Ranolazine Assessed as Cronbach's Alpha Value | Baseline to Week 4 | Reliability of the WISQ was assessed by estimating Cronbach's alpha (standardized); values of 0.7 or higher were to be considered adequate. (Standardized Cronbach's alpha is a coefficient of reliability or consistency, and is a function of the average inter-item correlation.) Cronbach's alpha was calculated for the WISQ instrument overall and for the Angina Frequency/Severity and Angina Stability subscales. Missing item responses were not imputed. |
| Evaluate the Responsiveness of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and NTG Consumption Before and Following Treatment With Ranolazine Assessed by Regression Analysis | Baseline to Week 4 | Responsiveness of the WISQ was assessed as the estimated coefficient of determination (R\^2) of the change from baseline WISQ Total Score at 4 weeks regressed on change from baseline angina frequency and change from baseline NTG use. For mean (SEM) Baseline and Week 4 values for angina frequency and NTG use, please refer to Secondary Outcome Measures 7 and 8. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine the Effect of Ranolazine on Angina Frequency as Measured by Patient-reported Diaries | Baseline to Week 4 | Angina episodes were recorded by subjects in their diaries. Weekly frequency of angina episodes was calculated for the two-week baseline period and the last two weeks of the study. |
| Determine the Effect of Ranolazine on Nitroglycerin Consumption as Measured by Patient-reported Diaries | Baseline to Week 4 | Nitroglycerin use was recorded by subjects in their diaries. Weekly frequency of NTG use was calculated for the two-week baseline period and the last two weeks of the study. |
| Determine Whether the WISQ is Noninferior to the Seattle Angina Questionnaire (SAQ) With Regard to Angina Frequency Items Based on Changes From Baseline (BL) in the Angina Frequency Items of the WISQ With the SAQ Following Ranolazine Treatment | Baseline to 4 Weeks | Changes from BL in angina frequency items following ranolazine treatment were measured. Analysis: multiple linear regression; response variable: ΔWISQ - ΔSAQ; independent variables: age and BL WISQ and SAQ scores. WISQ items: 15 points (higher=more severe state); SAQ items: 12 points (lower=more severe state). WISQ scores were recalibrated by multiplying by .75. Noninferiority was to be considered demonstrated if the lower limit of a 2-sided 95% CI for WISQ mean - SAQ mean was above the prespecified margin (WISQ vs SAQ difference of -2). |
| Evaluate the Degree of Correlation Between Changes From Baseline in Items of the WISQ and SAQ With Changes From Baseline in Angina Frequency and NTG Diary Data and the DASI | Baseline to Week 4 | The DASI is a self-administered questionnaire that measures a patient's functional capacity. It can be used to get a rough estimate of a patient's peak oxygen uptake. The maximum score for the DASI is 58.2 (better functional ability/capacity) and the minimum score is 0 (worse functional ability/capacity). The planned analysis was the amount of variation in WISQ and SAQ score changes from baseline explained by changes in angina frequency, NTG use, and DASI score assessed by multiple linear regression analysis. |
| Determine Changes From Baseline in the Duke Activity Status Index (DASI) Following Ranolazine Treatment | Baseline to Week 4 | The DASI was analyzed as mean values at baseline and Week 4. The DASI is a self-administered questionnaire that measures a patient's functional capacity. It can be used to get a rough estimate of a patient's peak oxygen uptake. The maximum score for the DASI is 58.2 (better functional ability/capacity) and the minimum score is 0 (worse functional ability/capacity). |
| Compare Changes From Baseline (BL) in the Physical Limitation Items of the WISQ With the SAQ Following Ranolazine Treatment | Baseline to 4 Weeks | Changes from BL in stress, excitement, temperature, satiety, anger, and other limitation items following ranolazine treatment were measured. Analysis: multiple linear regression; response variable: ΔWISQ - ΔSAQ; independent variables: age and BL WISQ and SAQ scores. WISQ items: 27 points (higher=more severe state); SAQ items: 45 points (lower=more severe state). WISQ scores were recalibrated by multiplying by 15/27. Noninferiority was to be considered demonstrated if the lower limit of a 2-sided 95% CI for WISQ mean - SAQ mean was above the prespecified margin (WISQ vs SAQ difference of -2). |
| Compare Changes From Baseline (BL) in Other Like Items of the WISQ With the SAQ Following Ranolazine Treatment | Baseline to 4 Weeks | Changes from BL in stress, excitement, temperature, satiety, anger, and other limitation items following ranolazine treatment were measured. Analysis: multiple linear regression; response variable: ΔWISQ - ΔSAQ; independent variables: age and BL WISQ and SAQ scores. WISQ items: 27 points (higher=more severe state); SAQ items: 45 points (lower=more severe state). WISQ scores were recalibrated by multiplying by 15/27. Noninferiority was to be considered demonstrated if the lower limit of a 2-sided 95% CI for WISQ mean - SAQ mean was above the prespecified margin (WISQ vs SAQ difference of -2). |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled at a total of 30 study sites in the US. The first patient was screened on 07 November 2007, and the last patient was screened on 06 December 2010. The last patient observation was on 20 January 2011.
Pre-assignment details
In the 2-week qualifying phase, patients continued antianginal medications without changing dose or frequency and completed questionnaires to document angina symptoms, treatment and status. Patients who had average angina frequency of ≥ 2 attacks/week during this phase and met all enrollment criteria were enrolled in the open-label treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| Ranolazine In the open-label treatment phase (approximately 4 weeks' duration), patients were given open-label ranolazine extended-release (ER) tablets 500 mg twice daily and continued to take their baseline antianginal medications. Patients completed self-administered questionnaires to document angina symptoms, response to antianginal treatment, and functional status. They also completed daily diaries to document the occurrence of angina episodes and NTG consumption. | 171 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Completion Status Unknown | 2 |
| Overall Study | Could Not Attend Scheduled Visits | 1 |
| Overall Study | Did Not Meet Eligibility Requirements | 1 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Ranolazine |
|---|---|
| Age Continuous | 64.6 years STANDARD_DEVIATION 12 |
| Body Mass Index | 29.5 kg/m^2 STANDARD_DEVIATION 6.3 |
| Race/Ethnicity, Customized Asian | 3 participants |
| Race/Ethnicity, Customized Black | 20 participants |
| Race/Ethnicity, Customized Caucasian | 143 participants |
| Race/Ethnicity, Customized Hispanic | 5 participants |
| Region of Enrollment United States | 171 participants |
| Sex: Female, Male Female | 171 Participants |
| Sex: Female, Male Male | 0 Participants |
| Weight | 76.7 kg STANDARD_DEVIATION 17.6 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 34 / 171 |
| serious Total, serious adverse events | 8 / 171 |
Outcome results
Primary
Evaluate the Reliability of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and NTG Consumption Before and Following Treatment With Ranolazine Assessed as Cronbach's Alpha Value
Reliability of the WISQ was assessed by estimating Cronbach's alpha (standardized); values of 0.7 or higher were to be considered adequate. (Standardized Cronbach's alpha is a coefficient of reliability or consistency, and is a function of the average inter-item correlation.) Cronbach's alpha was calculated for the WISQ instrument overall and for the Angina Frequency/Severity and Angina Stability subscales. Missing item responses were not imputed.
Time frame: Baseline to Week 4
Population: Modified Intent-to-Treat Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ranolazine | Evaluate the Reliability of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and NTG Consumption Before and Following Treatment With Ranolazine Assessed as Cronbach's Alpha Value | WISQ Overall | 0.851 ratio of variances |
| Ranolazine | Evaluate the Reliability of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and NTG Consumption Before and Following Treatment With Ranolazine Assessed as Cronbach's Alpha Value | WISQ Angina Stability | 0.308 ratio of variances |
| Ranolazine | Evaluate the Reliability of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and NTG Consumption Before and Following Treatment With Ranolazine Assessed as Cronbach's Alpha Value | WISQ Angina Frequency | 0.794 ratio of variances |
Primary
Evaluate the Responsiveness of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and NTG Consumption Before and Following Treatment With Ranolazine Assessed by Regression Analysis
Responsiveness of the WISQ was assessed as the estimated coefficient of determination (R\^2) of the change from baseline WISQ Total Score at 4 weeks regressed on change from baseline angina frequency and change from baseline NTG use. For mean (SEM) Baseline and Week 4 values for angina frequency and NTG use, please refer to Secondary Outcome Measures 7 and 8.
Time frame: Baseline to Week 4
Population: Modified Intent-to-Treat Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranolazine | Evaluate the Responsiveness of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and NTG Consumption Before and Following Treatment With Ranolazine Assessed by Regression Analysis | 0.080 coefficient of determination |
Primary
Evaluate the Validity of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and Nitroglycerin (NTG) Consumption Before and Following Treatment With Ranolazine Assessed as Coefficient of Determination (R^2)
Validity of the WISQ was assessed by regression analysis. Results of this analysis are reported as the estimated coefficient of determination (R\^2) of the WISQ Total Score at 4 weeks regressed on 4-week angina frequency, 4-week NTG use, and DASI score at 4 weeks. For mean (SEM) Baseline and Week 4 values for angina frequency and NTG use, please refer to Secondary Outcome Measures 7 and 8. For mean (SEM) Baseline and Week 4 DASI values, please refer to Secondary Outcome Measure 9.
Time frame: Baseline to Week 4
Population: Modified Intent-to-Treat Analysis Set, defined as all patients who took at least 1 dose of ranolazine and completed both baseline and postbaseline questionnaires. Partially missing questionnaire responses were imputed by the methods specified in the scoring instructions; completely missing responses were not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranolazine | Evaluate the Validity of the WISQ in Women With Chronic Angina Based on Changes in Patient-reported Angina Frequency and Nitroglycerin (NTG) Consumption Before and Following Treatment With Ranolazine Assessed as Coefficient of Determination (R^2) | 0.337 coefficient of determination |
Secondary
Compare Changes From Baseline (BL) in Other Like Items of the WISQ With the SAQ Following Ranolazine Treatment
Changes from BL in stress, excitement, temperature, satiety, anger, and other limitation items following ranolazine treatment were measured. Analysis: multiple linear regression; response variable: ΔWISQ - ΔSAQ; independent variables: age and BL WISQ and SAQ scores. WISQ items: 27 points (higher=more severe state); SAQ items: 45 points (lower=more severe state). WISQ scores were recalibrated by multiplying by 15/27. Noninferiority was to be considered demonstrated if the lower limit of a 2-sided 95% CI for WISQ mean - SAQ mean was above the prespecified margin (WISQ vs SAQ difference of -2).
Time frame: Baseline to 4 Weeks
Population: Modified Intent-to-Treat Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranolazine | Compare Changes From Baseline (BL) in Other Like Items of the WISQ With the SAQ Following Ranolazine Treatment | -6.0 SAQ scale units |
Secondary
Compare Changes From Baseline (BL) in the Physical Limitation Items of the WISQ With the SAQ Following Ranolazine Treatment
Changes from BL in stress, excitement, temperature, satiety, anger, and other limitation items following ranolazine treatment were measured. Analysis: multiple linear regression; response variable: ΔWISQ - ΔSAQ; independent variables: age and BL WISQ and SAQ scores. WISQ items: 27 points (higher=more severe state); SAQ items: 45 points (lower=more severe state). WISQ scores were recalibrated by multiplying by 15/27. Noninferiority was to be considered demonstrated if the lower limit of a 2-sided 95% CI for WISQ mean - SAQ mean was above the prespecified margin (WISQ vs SAQ difference of -2).
Time frame: Baseline to 4 Weeks
Population: Modified Intent-to-Treat Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranolazine | Compare Changes From Baseline (BL) in the Physical Limitation Items of the WISQ With the SAQ Following Ranolazine Treatment | 12.2 SAQ scale units |
Secondary
Determine Changes From Baseline in the Duke Activity Status Index (DASI) Following Ranolazine Treatment
The DASI was analyzed as mean values at baseline and Week 4. The DASI is a self-administered questionnaire that measures a patient's functional capacity. It can be used to get a rough estimate of a patient's peak oxygen uptake. The maximum score for the DASI is 58.2 (better functional ability/capacity) and the minimum score is 0 (worse functional ability/capacity).
Time frame: Baseline to Week 4
Population: Modified Intent-to-Treat Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Determine Changes From Baseline in the Duke Activity Status Index (DASI) Following Ranolazine Treatment | Baseline | 23.9 DASI scale units | Standard Error 1.1 |
| Ranolazine | Determine Changes From Baseline in the Duke Activity Status Index (DASI) Following Ranolazine Treatment | Week 4 | 26.8 DASI scale units | Standard Error 1.1 |
Secondary
Determine the Effect of Ranolazine on Angina Frequency as Measured by Patient-reported Diaries
Angina episodes were recorded by subjects in their diaries. Weekly frequency of angina episodes was calculated for the two-week baseline period and the last two weeks of the study.
Time frame: Baseline to Week 4
Population: Modified Intent-to-Treat Analysis Set~Missing values were excluded
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Determine the Effect of Ranolazine on Angina Frequency as Measured by Patient-reported Diaries | Baseline | 7.9 attacks per week | Standard Error 0.7 |
| Ranolazine | Determine the Effect of Ranolazine on Angina Frequency as Measured by Patient-reported Diaries | Week 4 | 3.2 attacks per week | Standard Error 0.6 |
Comparison: Mean change in angina frequency from Baseline to Week 4
Secondary
Determine the Effect of Ranolazine on Nitroglycerin Consumption as Measured by Patient-reported Diaries
Nitroglycerin use was recorded by subjects in their diaries. Weekly frequency of NTG use was calculated for the two-week baseline period and the last two weeks of the study.
Time frame: Baseline to Week 4
Population: Modified Intent-to-Treat Analysis Set~Missing values were excluded
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Determine the Effect of Ranolazine on Nitroglycerin Consumption as Measured by Patient-reported Diaries | Baseline | 4.3 uses per week | Standard Error 0.5 |
| Ranolazine | Determine the Effect of Ranolazine on Nitroglycerin Consumption as Measured by Patient-reported Diaries | Week 4 | 1.1 uses per week | Standard Error 0.2 |
Comparison: Mean change in NTG use from Baseline to Week 4
Secondary
Determine Whether the WISQ is Noninferior to the Seattle Angina Questionnaire (SAQ) With Regard to Angina Frequency Items Based on Changes From Baseline (BL) in the Angina Frequency Items of the WISQ With the SAQ Following Ranolazine Treatment
Changes from BL in angina frequency items following ranolazine treatment were measured. Analysis: multiple linear regression; response variable: ΔWISQ - ΔSAQ; independent variables: age and BL WISQ and SAQ scores. WISQ items: 15 points (higher=more severe state); SAQ items: 12 points (lower=more severe state). WISQ scores were recalibrated by multiplying by .75. Noninferiority was to be considered demonstrated if the lower limit of a 2-sided 95% CI for WISQ mean - SAQ mean was above the prespecified margin (WISQ vs SAQ difference of -2).
Time frame: Baseline to 4 Weeks
Population: Modified Intent-to-Treat Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranolazine | Determine Whether the WISQ is Noninferior to the Seattle Angina Questionnaire (SAQ) With Regard to Angina Frequency Items Based on Changes From Baseline (BL) in the Angina Frequency Items of the WISQ With the SAQ Following Ranolazine Treatment | -0.035 ratio of variance |
Secondary
Evaluate the Degree of Correlation Between Changes From Baseline in Items of the WISQ and SAQ With Changes From Baseline in Angina Frequency and NTG Diary Data and the DASI
The DASI is a self-administered questionnaire that measures a patient's functional capacity. It can be used to get a rough estimate of a patient's peak oxygen uptake. The maximum score for the DASI is 58.2 (better functional ability/capacity) and the minimum score is 0 (worse functional ability/capacity). The planned analysis was the amount of variation in WISQ and SAQ score changes from baseline explained by changes in angina frequency, NTG use, and DASI score assessed by multiple linear regression analysis.
Time frame: Baseline to Week 4
Population: Data was collected for this outcome, however, the analysis was not done.