Summary

• In the CREDENCE study, INVOKANA was found to significantly reduce the rates of the primary composite outcome of end-stage kidney disease (ESKD), doubling of serum creatinine (dSCr), and renal or cardiovascular (CV) death (43.2 and 61.2 per 1000 patient years [PY] in the INVOKANA and placebo (PBO) arms, respectively), resulting in a 30% relative risk reduction (RRR) (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.59–0.82; P=0.00001; number needed to treat [NNT]=22 over 2.5 years.^{1, 2}
  • In the CREDENCE study, INVOKANA significantly reduced the risk of:¹
    • The composite of CV death and hospitalization for heart failure (HHF; RRR, 31%; HR, 0.69; 95% CI, 0.57-0.83; P<0.001)
    • In a secondary analysis, the effect of INVOKANA on CV death or HHF did not show significant differences when evaluated by baseline age, sex, history of CV disease, history of heart failure (HF), estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), or loop diuretic use (all P interactions >0.2 for HRs).³
    • The composite of major adverse cardiovascular events (MACE), comprised of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke (RRR 20%; HR, 0.80; 95% CI, 0.67-0.95; P=0.01)
    • HHF (RRR 39%; HR 0.61; 95% CI 0.47-0.80; P<0.001)
  • The risk of CV death was not found to be statistically significant (HR, 0.78; 95% CI, 0.61-1.00; P=0.0502), therefore, due to the hierarchical testing sequence, the remaining secondary endpoints were not formally tested.¹
  • All-cause mortality (HR, 0.83; 95% CI, 0.68-1.02)
  • CV composite of CV death, MI, stroke, HHF, or unstable angina (HR, 0.74; 95% CI, 0.63 to 0.86)
• A pot hoc analysis of the CREDENCE study evaluated the kidney, CV, and safety outcomes by age groups and sex.⁴
  • The effect of INVOKANA on CV outcomes (including CV death, MACE, and HF) was consistent across subgroups of age (CV death, P_interaction=0.2; MACE, P_interaction=0.1; HF, P_interaction=0.7) and sex (CV death, P_interaction=0.7; MACE, P_interaction=0.5; HF, P_interaction=0.9).  
• In the CREDENCE study, INVOKANA significantly reduced CV outcomes in both the primary and the secondary prevention cohorts. Patients were classified as secondary prevention if they had a history of coronary, cerebrovascular, or peripheral vascular disease at baseline. All other participants belonged to the primary prevention cohort:²
  • Analyses for the primary outcome in primary and secondary prevention cohorts were prespecified. Additional analyses were post hoc.²
  • The composite of CV death or HHF was reduced in both the primary (HR, 0.74; 95% CI, 0.54-1.03) and secondary (HR, 0.66; 95% CI, 0.52-0.83) prevention groups; with no evidence of heterogeneity between groups (P interaction 0.57).
  • The composite of MACE was reduced in both the primary (HR, 0.68; 95% CI, 0.490.94) and secondary (HR, 0.85; 95% CI, 0.69-1.06) prevention groups; with no evidence of heterogeneity between groups (P interaction 0.25).
  • The HHF was reduced in both the primary (HR, 0.61; 95% CI, 0.39-0.96) and secondary (HR, 0.61; 95% CI, 0.44-0.85) prevention groups; with no evidence of heterogeneity between groups (P interaction 0.98).
• In the CANVAS Program,^{5, 6} INVOKANA met the primary outcome by significantly reducing the rates of the composite of MACE at 26.9 vs 31.5 per 1000 PY (HR, 0.86; 95% CI 0.75-0.97; P<0.0001 for noninferiority; P=0.0158 for superiority) when compared with PBO, respectively.
  • All three components of the MACE composite endpoint exhibited point estimates of effect suggesting benefit with INVOKANA.⁵
    • CV death occurred at a rate of 11.6 and 12.8 per 1000 PY in the INVOKANA and PBO groups, respectively; the nominal effect estimates were (HR, 0.87; 95% CI, 0.72-1.06).⁵
    • Non-fatal MI occurred at a rate of 9.7 and 11.6 per 1000 PY in the INVOKANA and PBO groups, respectively; the nominal effect estimates were (HR, 0.85; 95% CI, 0.69-1.05).⁵
    • Non-fatal stroke occurred at a rate of 7.1 and 8.4 per 1000 PY in the INVOKANA and PBO groups, respectively; the nominal effect estimates were (HR, 0.90; 95% CI, 0.71-1.15).⁵
  • INVOKANA was associated with protection against HHF at 5.5 and 8.7 events per 1000 PY compared to PBO, respectively (HR, 0.67; 95% CI, 0.52-0.87).⁵

CREDENCE

CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), was a randomized, double-blind, PBO-controlled, parallel group multicenter, event-driven clinical study to assess the effects of INVOKANA (100 mg) compared to PBO on clinically important renal outcomes in patients with type 2 diabetes mellitus (T2DM) and established chronic kidney disease (CKD) (eGFR 30 to <90 mL/min/1.73m²) and albuminuria (ratio of albumin to creatinine >300 to 5000 mg/g), who were receiving a stable, maximum tolerated or labelled dose (for >4 weeks prior to randomization) of an angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB).^{1, 7-11}

• Patients who were eligible to participate in the study were ≥30 years with T2DM (HbA1c ≥6.5% to ≤12.0%; participants in Germany required a HbA1c range of ≥6.5% to <10.5%), had CKD, and an eGFR 30 to <90 mL/min/1.73m² and albuminuria (UACR >300 to 5000 mg/g).^{1, 9}
• Patients who were excluded from participating in the study included, but were not limited to, those with a history of CV events within the previous 12 weeks or a history of New York Heart Association class IV HF at any time.^{1, 7, 9}
• Patients were randomly assigned in a 1:1 ratio to either INVOKANA 100 mg or matching PBO using randomly permuted blocks with stratification by baseline eGFR categories (30 to <45, 45 to <60, and 60 to <90 mL/min/1.73 m²).
• Use of other therapies for glycemic management and CV risk factor control was recommended in accordance with clinical practice guidelines.

Outcomes

• The primary endpoint was the composite of ESKD (defined as chronic dialysis for >30 days, renal transplantation, or eGFR <15 mL/min/1.73m² sustained for >30 days), the dSCr from baseline average sustained for >30 days, and death due to renal or CV disease.
• Secondary outcomes were planned for sequential hierarchical testing. If INVOKANA was superior to PBO for reducing the risk of the primary efficacy endpoint, the treatment effects in the secondary endpoints would be tested subsequently. Statistical significance was required before testing the next hypothesis in the hierarchical test procedure in the following order:⁷
  • Composite of CV death or HHF
  • Composite of MACE, comprised of CV death, nonfatal MI, and nonfatal stroke
  • HHF
  • Renal-specific composite of ESKD, dSCr, or renal death
  • CV death
  • All-cause mortality
  • Expanded CV composite of CV death, nonfatal MI, nonfatal stroke, HHF, or hospitalized for unstable angina
• Prespecified exploratory endpoints included, but were not limited to: composite endpoint of ESKD, renal or CV death; fatal and nonfatal MI; fatal and nonfatal stroke; and hospitalized for unstable angina.⁷
• All renal and CV events that were components of the primary and secondary composite endpoints of the study and all key safety outcomes (bone fractures, pancreatitis, ketoacidosis, renal cell carcinoma [RCC]) were adjudicated by independent blinded adjudication committees.⁷

Baseline Characteristics

• A total of 4401 participants were randomized from 690 sites across 34 countries between March 2014 and May 2017 in the intention-to-treat (ITT) analysis set. There were 4 participants that were not dosed, leading to 4397 participants in the on-treatment and on-study analysis sets.
• Baseline characteristics were similar between the INVOKANA and PBO groups. These included a mean age of 63 years, 66% male participants, mean duration of T2DM of 15.8 years; mean HbA1c of 8.3%, mean eGFR of 56.2 mL/min/1.73m², median UACR of 927 mg/g; 50.4% had prior CV disease, 14.8% had a history of HF.⁷
• Across both treatment groups, the mean exposure to study drug was 115 weeks.
• For more information related to the CREDENCE baseline characteristics, please refer to Table: CREDENCE: Select Baseline Characteristics.

Results

By July 2018, the number of confirmed primary endpoints to trigger the planned interim analysis had been accrued and the prespecified efficacy criteria for early cessation had been achieved. The independent data monitoring committee advised the Steering Committee to end the CREDENCE study early after a median follow-up duration of 2.62 years (range 0.024.53 years).¹

• A total of 4361 (99.1%) of participants were followed until the study completion for clinical and safety endpoints. Final vital status was collected in 99.9% of participants.¹
• The most frequent reason for study discontinuation was an adverse event (AE; 12% and 13% of INVOKANA and PBO groups, respectively).¹

Primary Outcome

• In the CREDENCE study, INVOKANA significantly reduced the rates of the composite outcome of ESKD, dSCr, and renal or CV death (43.2 and 61.2 per 1000 PY in the INVOKANA and PBO arms, respectively), resulting in a 30% RRR (HR, 0.70; 95% CI, 0.59–0.82; P=0.00001; NNT=22 over 2.5 years for the primary composite endpoint). See Figure: Time to First Occurrence: Primary Composite Outcome and Table: Number Needed to Treat.¹

CV Death Component of the Primary Composite Outcome

• • The event rate of CV death was 19.0 and 24.4 per 1000 PY (HR, 0.78; 95% CI, 0.611.00) in the INVOKANA and PBO groups, respectively.¹ See Figure: Time to First Occurrence: CV Death and Table: Summary of Efficacy Results.

Secondary and Exploratory Outcomes

• In the CREDENCE study, INVOKANA significantly reduced the risk of:¹
  • The composite of CV death and HHF (RRR, 31%; HR, 0.69; 95% CI, 0.57-0.83; P<0.001)
  • MACE (CV death, nonfatal MI, or nonfatal stroke) (RRR, 20%; HR, 0.80; 95% CI, 0.670.95; P=0.01)
  • HHF (RRR, 39%; HR, 0.61; 95% CI, 0.47-0.80; P<0.001)
  • See Figures: Rates of CV death or HHF / MACE / HHF in CREDENCE (A, B, C) and Table: Number Needed to Treat.
• The risk of CV death was not found to be statistically significant (P=0.0502), therefore, due to the hierarchical testing sequence, the remaining two secondary endpoints were not formally tested.¹ See Table: Summary of Efficacy Results.

Safety & Intermediate Outcomes

• In the CREDENCE study, the overall rates of AEs and serious AEs, (on-treatment and onstudy analysis sets), were similar between the treatment groups.¹
• INVOKANA treatment demonstrated a greater mean change in systolic blood pressure
  (-3.30 mmHg; 95% CI, -2.73 to -3.87 mmHg), diastolic blood pressure (-0.95 mmHg; 95% CI, -0.61 to -1.28 mmHg), and body weight (-0.80 kg; 95% CI, -0.69 to -0.92 kg).¹

Primary and Secondary Prevention

Analyses for the primary outcome in primary and secondary prevention cohorts were prespecified and originally presented at the American Diabetes Association 79^th Annual Scientific Sessions in June 2019.¹² Patients were classified as secondary prevention if they had a history of coronary, cerebrovascular, or peripheral vascular disease at baseline. All other participants belonged to the primary prevention cohort. Analyses for the primary outcome in primary and secondary prevention cohorts were prespecified, but additional analyses were post hoc.²

A total of 2181 (49.6%) participants had no history of documented CV disease at entry and were in the primary prevention group, and 2220 (50.4%) participants were in the secondary prevention group. Primary prevention participants were younger (61.4 vs 64.6 years), more often female (36.6% vs 31.3%), and Asian (24.4% vs 15.5%), with a shorter duration of diabetes (15.2 vs 16.4 years) compared to secondary prevention participants. Primary and secondary prevention participants had similar mean eGFR (56.8 vs 55.5 mL/min/1.73 m²) and median UACR (943 vs 903 mg/g).²

INVOKANA significantly reduced CV outcomes, with no evidence of heterogeneity in the primary and secondary prevention groups (all interaction P values not significant).² See Table: CREDENCE CV Outcomes in the Primary, Secondary, and Overall Populations.

Secondary Analyses of the CREDENCE Study

Arnott et al (2020)³ conducted a secondary analysis of the pre-specified, hierarchical, secondary outcome HHF or CV death by patient baseline characteristics including age (>65 or <65), sex (male [M]/female [F]), history of CV disease (yes [Y]/no [N]), history of HF or corresponding New York Heat Association (NYHA) functional classification (no HF or NYHA I-III), eGFR (30 to <45, 45 to <60, and 60 to <90 mL/min/1.73m²), UACR (>1000 or <1000), and baseline diuretic use (Y/N). In the CREDENCE study, 432 patients experienced an HHF/CV event over a median follow-up of 2.6 years. The effect of INVOKANA on CV death or HHF did not show significant differences by these baseline subgroups (all P interactions >0.2 for HRs).

Post Hoc Analysis of the CREDENCE Study

Yi et al (2023)⁴ conducted a post hoc analysis to evaluate the kidney, CV, and safety outcomes by age groups and sex in patients from the CREDENCE study.

• Of the 4401 patients who were randomized, 1475, 1854, and 1072 were aged <60 years, 6069 years, and ≥70 years, respectively. Overall, 2907 patients were male, and 1494 patients were female.
• The mean age of patients was 63 (standard deviation [SD], 9.2) years, and the median follow-up duration was 2.62 years.
• The event rates of CV death in INVOKANA vs PBO were 14.3 vs 19.7, 17.8 vs 27.6, and 27.5 vs 25.4 in patients aged <60 years, 60-69 years, and ≥70 years, respectively. The event rates of MACE in INVOKANA vs PBO were 32.1 vs 38.4, 36.0 vs 55.4, and 52.9 vs 51.5 and those of HF were 9.6 vs 15.8, 17.0 vs 30.4, and 21.5 vs 29.9 in patients aged <60 years, 60-69 years, and ≥70 years, respectively, see Table: Effects of INVOKANA on CV Events by Age.
• The event rates of CV death in INVOKANA vs PBO were 19.3 vs 23.2 and 18.8 vs 25.0 in female and male patients, respectively. The event rates of MACE in INVOKANA vs PBO were 37.7 vs 42.9 and 39.2 vs 51.5 and those of HF were 16.0 vs 25.5 and 15.5 vs 25.3 in female and male patients, respectively, see Table: Effects of INVOKANA on CV Events by Sex.

The CANVAS Program

The CANVAS Program^{5, 6} (N=10,142) included a pre-specified integrated analysis of CANVAS^{13, 14} and CANVAS-R^{15, 16} to meet the Food and Drug Administration (FDA) postmarketing requirement (PMR) to determine CV safety, as well as evaluate the potential for CV protection with INVOKANA in T2DM patients who had either a prior history of CV disease or at least two CV risk factors.^{5, 6} These two studies were similar in design, patient population, procedures and assessments.^{5, 6}

• The CANVAS study was a randomized, double-blind, PBO-controlled, parallel group, multicentered, phase 3, event-driven study evaluating the CV risk for MACE, including CV death, nonfatal MI, and nonfatal stroke with INVOKANA.² The effects of INVOKANA relative to PBO on the risk of CV disease were assessed in patients on background standard of care (including metformin). Safety and tolerability were also evaluated.^{6, 13, 14}
  • Participants were randomized in a 1:1:1 ratio to INVOKANA 100 mg, INVOKANA 300 mg, or matching PBO.
• The CANVAS-R study was a randomized, double-blind, PBO-controlled, parallel group, multicentered, phase 4 study which assessed the effect of INVOKANA compared to PBO on progression of albuminuria in T2DM patients, who had either a prior history of CV disease or ≥2 CV risk factors. CANVAS-R was conducted in response to the FDA regulatory requirement for a “CANVAS-like” study, the data from which could be combined with data from CANVAS to satisfy post-marketing safety requirements for the incidence of MACE.^{6, 15, 16}
  • Participants were randomized in a 1:1 ratio to an initial dose of INVOKANA 100 mg or matching PBO. Optional up-titration to 300 mg (or matching PBO) was encouraged at week 13 (or thereafter) if additional glycemic control was required and the patient was tolerating the initial dose.

Endpoints

• The primary CV safety endpoint was time to first occurrence of MACE, a composite of CV death, nonfatal MI, or nonfatal stroke.
• Prespecified secondary endpoints planned for sequential hypothesis testing included but were not limited to: all-cause mortality (ACM), CV death, progression of albuminuria and the composite of CV death and HHF based on either a truncated integrated dataset or CANVAS-R alone dataset.⁵
• Exploratory prespecified CV outcomes were nonfatal MI, nonfatal stroke, and HHF, and the composite of CV death or HHF.⁵
• The analysis of these exploratory CV outcomes, death and hospitalizations were prespecified based on the full integrated dataset comprising of all randomized patients.⁵

Statistical Analysis

• The primary CV safety hypothesis test was of non-inferiority for the HR <1.3 for the primary outcome for all INVOKANA vs PBO using the full integrated CANVAS Program dataset and the ITT method. Additionally, superiority of INVOKANA would be demonstrated if the null hypothesis is rejected and the upper bound of the 2-sided 95% CI of the HR is also <1.0.^{5, 6}
• A sequential hypothesis testing process was utilized for the endpoints conditional on the primary safety hypothesis and each subsequent test for superiority being met in the full integrated dataset, a truncated dataset or the CANVAS-R dataset.⁵ If the sequential hypothesis testing was not significant for all outcomes specified, then the remaining outcomes were assessed as exploratory variables using the full integrated CANVAS Program dataset comprising of all randomized patients. P values for efficacy were reported only where the hypothesis was proven.⁵

Hypothesis testing of the mortality, and HHF outcomes in the sequential hypothesis testing plan were not to be done beyond the first nonsignificant result. For all subsequent and exploratory outcomes, reporting was conducted using the HR estimates and nominal 95% CIs.⁵ See Figure: The CANVAS Program: Sequential Hypothesis Testing Plan.

Inclusion Criteria

• Men and women with inadequately controlled T2DM (hemoglobin A1C [A1C] ≥7.0 and ≤10.5%) and at an elevated risk of CV disease who were either:^{5, 6}
  • Patients ≥30 years with documented symptomatic atherosclerotic CV disease defined as stroke, MI, hospital admission for unstable angina, coronary artery bypass graft, percutaneous coronary intervention (with or without stenting), peripheral revascularization (angioplasty or surgery), symptomatic with documented hemodynamically significant carotid or peripheral vascular disease, or amputation secondary to vascular disease (secondary prevention cohort).^{5, 6}
  • Patients ≥50 years with no prior CV events, but ≥2 CV risk factors: duration of T2DM ≥10 years, systolic blood pressure >140 mmHg while on ≥1 antihypertensive agents, current daily smoker, micro or macroalbuminuria, or high-density lipoprotein cholesterol (HDL-C) <1 mmol/L (39 mg/dL) (primary prevention cohort).^{5, 6}
• All participants were required to have a baseline eGFR>30 mL/min/1.73 m^{2,5, 6}

Baseline Characteristics

• Baseline characteristics were similar for both treatment groups in the CANVAS Program. Approximately 71% of CANVAS-R patients treated with INVOKANA were up-titrated to the 300 mg dose. Approximately 72.2% reported a history of atherosclerotic vascular disease and 65.6% reported a history of CV disease (secondary prevention cohort) in the CANVAS Program. Use of background therapy for glycemic and other risk factor management was according to best practice instituted within local guidelines.⁵

For more information related to The CANVAS Program baseline characteristics, please refer to Table: The CANVAS Program Baseline Characteristics.

Results

CV Safety and Efficacy Outcomes

• In the CANVAS Program, INVOKANA significantly reduced the rates of the composite of MACE, comprised of CV mortality, nonfatal MI, and nonfatal stroke (26.9 vs 31.5 per 1000 PY, HR, 0.86; 95% CI, 0.75-0.97; P<0.0001 for noninferiority; P=0.0158 for superiority) when compared with PBO.⁵ See Figure: Effect of INVOKANA on MACE in the CANVAS Program.

• All three components of the MACE composite endpoint reported point estimates of effect suggesting benefit with INVOKANA.⁵
  • CV death occurred at a rate of 11.6 and 12.8 events per 1000 PY (HR, 0.87; 95% CI, 0.72-1.06) in the INVOKANA and PBO groups, respectively.⁵
  • Nonfatal MI occurred at a rate of 9.7 and 11.6 events per 1000 PY (HR, 0.85; 95% CI, 0.69-1.05) in the INVOKANA and PBO groups, respectively.⁵
  • Nonfatal stroke occurred at a rate of 7.1 and 8.4 events per 1000 PY (HR, 0.90; 95% CI, 0.71-1.15) in the INVOKANA and PBO groups, respectively.⁵
    • The direction of stroke effect observed in the CANVAS Program differs from previous reports^9-12 of a possible adverse effect on stroke risk.⁵ See Table: The CANVAS Program: Effect of INVOKANA vs PBO for CV Outcomes, Death, and Hospitalization. Additionally, see Figure: The CANVAS Program: Effects of INVOKANA vs PBO on CV, Renal, Hospitalization, and Death Events.
• Overall, consistent effects for the MACE composite endpoint across a broad range of prespecified subgroups were reported (P<0.001 for homogeneity; see Figure 4 within the published paper).⁵
• INVOKANA was associated with protection against HHF at 5.5 and 8.7 per 1000 PY in the INVOKANA and PBO groups, respectively, (HR, 0.67; 95% CI, 0.52-0.87).⁵
• The composite endpoint of CV death or HHF occurred at a rate of 16.3 and 20.8 events per 1000 PY in the INVOKANA and PBO groups, respectively, (HR, 0.78; 95% CI, 0.670.91).⁵
• In the full integrated dataset, nominal effect estimates for ACM were HR, 0.87; 95% CI, 0.74-1.01 and for CV death were HR, 0.87; 95% CI, 0.72-1.06.⁵ See Table: The CANVAS Program: Effect of INVOKANA vs PBO for CV Outcomes, Death, and Hospitalization. Additionally, see Figure: The CANVAS Program: Effects of INVOKANA vs PBO on CV, Renal, Hospitalization, and Death Events.

• In the hypothesis testing sequence, superiority of INVOKANA was not demonstrated for the first secondary outcome in reducing ACM (using truncated dataset), therefore, hypothesis testing of the other outcomes in the sequence was not done and nominal effect estimates were calculated for all subsequent and exploratory outcomes.⁵ For additional information regarding the results for the prespecified sequential hypothesis testing plan, see Table: The CANVAS Program: Results for the Prespecified Sequential Hypothesis Testing Plan.

Overall Safety

• The AEs reported in the CANVAS Program are generally consistent with the known safety profile of INVOKANA. Serious AEs were reported less frequently with INVOKANA vs PBO (104.25 vs 120.02 per 1000 PY); HR, 0.93; 95% CI, 0.87-1.00; P<0.05.⁵ The incidence of AEs leading to discontinuation was higher for INVOKANA vs PBO (35.49 vs 32.76 per 1000 PY; HR, 1.13; 95% CI, 0.99-1.28).⁵

Subgroup Analyses of the CANVAS Program

Several subgroup analyses of the CANVAS Program data have been conducted for CV, renal, and/or safety outcomes for patients based on history of CV disease¹⁷, history of HF,¹⁸ and baseline kidney function.^{19, 20}

Radholm et al (2018)²¹ reported sub-group analyses of the CANVAS Program which compared INVOKANA vs PBO among 14.4% of patients with HF at baseline (n=1461) and among the 85.6% of patients without HF at baseline (n=8681). The primary composite outcome for this subgroup analysis of patients with or without HF was adjudicated CV death or HHF.

Results

CV Death/HHF

• Among 1461 patients with HF at baseline in the CANVAS Program, 203 had CV death or HHF events. INVOKANA was associated with lower risk of CV death or HHF compared to PBO, with an annualized incidence rates of 35.4 and 56.8 per 1000 PY, respectively (HR, 0.61; 95% CI, 0.46-0.80).²¹
• Among 8681 patients without HF at baseline in the CANVAS Program, 449 had CV death or HHF events with an annualized incidence rate of 13.6 and 15.2 per 1000 PY, respectively (HR, 0.87 95% CI, 0.72-1.06).²¹
• The benefit on CV death or HHF was significantly greater in patients with a prior history of HF compared with those without HF at baseline (interaction P value=0.021).

HHF alone

• In patients with HF at baseline (n=1461), INVOKANA was associated with lower risk of HHF compared to PBO, with an annualized incidence rates of HHF were 14.1 and 28.1 per 1000 PY, respectively (HR, 0.51; 95% CI, 0.33-0.78)
• In patients without HF at baseline (n=8681), the annualized incidence rates of HHF were 4.3 and 5.7 per 1000 PY in the INVOKANA and PBO groups, respectively (HR, 0.79; 95% CI, 0.57-1.09)
• The benefit on HHF did not show statistical evidence of heterogeneity in patients with a prior history of HF compared with those without HF at baseline (interaction P value=0.47).
• The NNT based on the annualized incidences rates reported above to prevent 1 HHF event in 5 years was substantially fewer in patients with prior history of HHF (1 in 14) compared to those without HF history (1 in 144).²²

Mahaffey et al (2017) ²³ reported a prespecified sub-group analyses of the CANVAS Program which compared the effect of INVOKANA vs PBO on the primacy composite endpoint and secondary outcomes among the 66% of patients with a history of atherosclerotic CV disease (n=6656) and the 34% of patients without prior history of atherosclerotic CV disease but with ≥2 CV risk factors (n=3486) at baseline.

• The primary composite endpoint of CV death, nonfatal MI, and nonfatal stroke occurred at a higher rate in the secondary prevention population vs the primary prevention (36.9 vs 15.7 events per 1000 PY; HR 2.36; 95% CI 2.03-2.74; P<0.001).
  • Individual components of the primary composite endpoint occurred at a higher rate in the secondary prevention group (P<0.001 for all three components).
• The primary composite endpoint was reduced with INVOKANA vs PBO in the total cohort (26.9 vs 31.5 per 1000 PY; HR, 0.86; 95% CI, 0.75-0.97; P<0.001 for noninferiority; P=0.02 for superiority). There was no evidence of heterogeneity between the primary and secondary prevention groups for the primary endpoint (P value for interaction=0.18) as well as for HHF (P value for interaction >0.10).
• See Table: CV Outcomes in the Total Population and the Primary and Secondary Prevention Cohorts.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 26 July 2023.