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Adverse Event - Amputation - Randomized Controlled Trials

Last Updated: 07/25/2023

SUMMARY

  • In the past, several health authorities have issued alerts on INVOKANA (CANA) and other sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of amputation.1, 2 3, 4 While several mechanisms behind the increase in amputation events associated with CANA in the CANVAS Program or other SGLT2 inhibitors in post-marketing surveillance have been postulated, at present, the consensus in the published medical literature is that the cause is yet unknown1-20.
    • One hypothesis for the mechanism is through drug-induced hypovolemia, as CANA has a mild diuretic action. The volume depletion and decreased tissue perfusion has been suggested to lead to tissue necrosis and lower limb amputations.20, 21
    • Another hypothesis proposes that amputations may be associated with increased hematocrit and blood viscosity or arterial thrombosis. 16, 17
    • Off-target activity of CANA related to specific chemical or pharmacologic properties that are not shared by other SGLT2 inhibitors have also been suggested.19
  • In August 2020, the U.S Food & Drug Administration (FDA) released a Drug Safety communication to remove the Boxed Warning on amputation risk from the INVOKANA U.S Prescribing Information (USPI). The Boxed Warning was initially required in 2017; however, subsequent reviews of new clinical data indicated that the risk of amputation was lower than previously described. Please refer to the local labeling for relevant information for INVOKANA.22
  • In CREDENCE, a large, randomized, double-blind study of patients with type 2 diabetes mellitus (T2DM) and albuminuric chronic kidney disease (CKD; N=4401), there was no statistical difference observed in the risk of atraumatic lower limb amputation between the CANA vs placebo arms (12.3 vs 11.2 events per 1000 patient-years [PYs]; hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.79-1.56).23
  • In the CANVAS Program (N=10,142), comprised of CANVAS and CANVAS-R, 2 large, randomized, placebo-controlled trials in patients with T2DM who had established cardiovascular disease (CVD) or were at risk for CVD, an increased risk of amputations with CANA vs placebo was observed (6.3 vs 3.4 per 1000 PYs; HR, 1.97; 95% CI, 1.41-2.75; P<0.001).24, 25
  • Matthews et al (2019)26 conducted a secondary analyses of amputation events from the CANVAS Program. The risk of amputation was observed with both the 100 mg and 300 mg daily dosage regimens. Overall amputation risk was associated with baseline history of prior amputation (major or minor; HR, 21.31; 95% CI, 15.40-29.49) and other established risk factors. No interactions between randomized treatment patient characteristics explained the effect of INVOKANA on amputation risk.
  • A pooled analysis of individual patient data from the CANVAS Program and CREDENCE study was conducted to evaluate the cardiovascular and renal outcomes of INVOKANA in patients with T2DM with and without peripheral arterial disease (PAD). The rate of amputation events per 1000 PYs in the INVOKANA and placebo groups were 25.21 and 20.02, respectively, for patients with PAD (HR, 1.37; 95% CI, 1.03-1.82) and 3.44 and 2.16, respectively, for patients without PAD (HR, 1.69; 95% CI, 1.12-2.54) (Pinteraction=0.313).27
  • In a pooled analysis evaluating the effect of CANA on amputation risk in the CANVAS Program and CREDENCE study, effects of CANA on amputation risk were significantly different between studies, with greater risk observed in CANVAS vs CREDENCE; however, no explanation for the difference in risk between the studies was identified.28
  • No increase in incidence of amputation was observed across 12 completed, phase 3 or 4 CANAclinical trials (N=8114), with a mean follow-up of 0.9 years.6, 29, 30

CLINICAL DATA

Phase 3 & 4 Studies

No increase in incidence of amputation was observed across 12 completed phase 3 or 4 CANA clinical trials (N=8114)31-46 with a mean follow-up of 0.9 years (rate of amputation in INVOKANA-treated individuals was 0.5 per 1000 PYs vs the rate in the placebo/comparator individuals of 2.2 per 1000 PYs).6

CREDENCE

  • CREDENCE (INVOKANA and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), was a randomized, double-blind, placebo-controlled, parallel-group multicenter, event driven clinical trial to assess the effects of CANA (100 mg) compared with placebo on clinically important renal outcomes in patients with T2DM and established CKD (estimated glomerular filtration rate [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 labelled dose (for >4 weeks prior to randomization) of an angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB).23, 47-51
  • Patients with a history of atraumatic amputation within the 12 months prior to screening, or an active skin ulcer, osteomyelitis, gangrene, or critical ischemia of the lower extremity within 6 months of screening were excluded from the study.47

Patients were randomly assigned in a 1:1 ratio to either CANA 100 mg or matching placebo 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).

  • Due to an increased risk of lower limb amputations in the CANVAS Program,25 an amendment was made to the CREDENCE protocol in May 2016, requiring investigators to:49
    • Provide or ensure that all subjects have had general foot self-care education.
    • Perform a comprehensive foot evaluation at each visit to identify risk factors for ulcers and amputations. The examination should include inspection of the skin, assessment of foot deformities, neurological assessment including pinprick or vibration testing or assessment of ankle reflexes, and vascular assessment including pulses in the legs and feet.
    • Refer subjects who have a history of prior lower extremity complications, loss of protective sensation, structural abnormalities, or peripheral arterial disease to foot care specialists for ongoing preventive care.
    • In participants who developed conditions associated with amputation (i.e., lower extremity infection, skin ulcer, osteomyelitis, gangrene, critical limb ischemia), the study drug was temporarily interrupted until the condition resolved in the opinion of the investigator. In the event of an amputation, restarting of dosing with CANA was only done after careful consideration of the individual risk: benefit.47, 49

Primary Outcome

  • The primary outcome was the composite of the following:23
    • End stage kidney disease (ESKD; defined as chronic dialysis for >30 days, renal transplantation, or eGFR <15 mL/min/1.73m2 sustained for >30 days)
    • Doubling of serum creatinine from baseline average sustained for >30 days
    • Death due to renal or CV disease
  • Amputation was designated as an adverse event (AEs) of interest to be collected.23, 47

Results

After a median follow-up of 2.62 years, the CREDENCE trial was stopped early for achieving the pre-specified criteria for the primary outcome (P<0.01) and the composite of ESKD or death from renal and CV causes (P<0.025).23, 47

Baseline Characteristics

  • Baseline characteristics were similar between the CANA and placebo groups.
    • The proportion of subjects with a history of amputation was similar between groups (5.4% in the CANA group and 5.2% in the placebo group).
  • Across both treatment groups, the mean exposure to study drug was 115 weeks.

Methodology for Capturing Amputation Events

Janssen designated all lower-extremity amputation procedures as an AE of special interest and required reporting of any amputation procedure within 24 hours of becoming aware of the procedure. Janssen created a designated Lower-Extremity Amputation electronic case report form (eCRF) where all details relating to the amputation procedure(s) must be recorded.

Results

  • In the CREDENCE study, there was no statistical difference observed in the risk of atraumatic lower limb amputation, which occurred at a rate at 12.3 (n=70/2200) vs. 11.2 (n=63/2197) in the CANA vs placebo arms (HR, 1.11; 95% CI, 0.79-1.56). See Figure: Lower-Extremity Amputation in the CREDENCE Study.23, 48

Lower-Extremity Amputation in the CREDENCE Study51

From: Perkovic V, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE). Data presented at the International Society of Nephrology: World Congress of Nephrology, 15 April 2019; Melbourne, Australia.  Reprinted with permission from The George Institute for Global Health. ©The George Institute for Global Health.

CANVAS Program

The CANVAS Program25 (N=10,142) comprises 2 large CANA CV outcome studies, CANVAS52, 53 and CANVAS-R54, 55, designed to meet FDA post-marketing requirement (PMR) to evaluate CV safety and efficacy of CANA in patients with T2DM who had either a prior history of CV disease or at least two CV risk factors.54-57 The mean duration of diabetes at baseline was 13.5 years 25

Baseline Characteristics

Baseline characteristics were similar in the CANA and placebo treatment groups and were comparable across CANVAS and CANVAS-R.

  • Smokers and patients with documented peripheral vascular disease (PVD) or amputation secondary to vascular disease were eligible to participate.52, 56
  • Determination of PVD or a history of amputation at baseline was based upon physician reporting without clinical evaluation or imaging.26
  • Patients with a history of amputations were included in the CANVAS Program. CANVAS: n=78 (1.8%), CANVAS-R: n=160 (2.8%).
  • Patients with a history of amputations across the entire CANVAS Program: CANA n=136 (2.3%), placebo=102 (2.3%).

Methodology for Capturing Amputation Events

During interim analysis of safety data from CANVAS, the IDMC identified amputation as a potential signal that should be further investigated.58Prior clinical or preclinical studies did not find any risk or concern for amputation with CANA.26 Before the interim analysis, amputation events and other AEs were recorded by investigators using electronic case record forms. Following the notification of the potential signal, in July 2016, a dedicated case report form (CRF) was created to prospectively and retroactively collect information on all cases of amputation. Additionally, all participant care records and the pharmacovigilance database were searched to identify additional possible events.

The proximate etiologies (infection, chronic, or acute ischemia) underlying each amputation event was evaluated in a secondary post hoc assessment by a specialist in peripheral vascular disease.26

Results

  • Mean follow-up was 188 weeks; the length of follow-up was similar in the CANA and placebo groups, but was longer in CANVAS (296 weeks) than in CANVAS-R (108 weeks).25
  • The CANVAS Program showed an increased risk of amputations with CANA vs placebo (6.3 vs 3.4 per 1000 PYs; HR, 1.97; 95% CI, 1.41-2.75; P<0.001).
  • The increased risk was seen with CANA 100-mg and 300-mg doses.24, 26 There is no evidence of a dose-response relationship.59
  • See Table: Amputation Events from the CANVAS Program, CANVAS, and CANVAS-R.

Amputation Events from the CANVAS Program, CANVAS, and CANVAS-R24, 25
Patients with amputation
n (%)

Total amputationsa
Amputation incidence
(per 1000 PYs)

HR (95% CI)
CANVAS Program25
PBO (N=4344)
47 (1.1)
69
3.4
1.97 (1.41-2.75)
CANA (N=5790)
140 (2.4)
221
6.3b
CANVAS24
PBO (N=1441)
22 (1.5)
33
2.8
-
CANA 100 mg (N=1445)
50 (3.5)
83
6.2
2.24 (1.36-3.69)
CANA 300 mg (N=1441)
45 (3.1)
79
5.5
2.01 (1.20-3.34)
CANA-Pooled (N=2886)
95 (3.3)
162
5.9
2.12 (1.34-3.38)
CANVAS-R24
PBO (N=2903)
25 (0.9)
36
4.2
1.80 (1.10-2.93)
CANAc (N=2904)
45 (1.5)
59
7.5
Abbreviations: CANA, INVOKANA; CI, confidence interval; HR, hazard ratio; PBO, placebo; PYs, patient-years.
aSome patients had more than one surgical amputation; bP<0.001 vs placebo. cInitial dose of CANA 100 mg with optional up-titration to 300 mg at 13 weeks.

Secondary Analyses of Amputation Events

Matthews et al (2019)26 conducted secondary analyses of amputation events from the integrated dataset of the CANVAS Program, apart from dose effects, which was done on the CANVAS study dataset alone.

Univariate associations were determined for risk factors for amputation independent of study drug, then those risk factors were included in a multivariate model that included the randomized treatment. The absolute effects of amputation (all events and major events) were modelled to estimate events for 1000 patients treated for 5 years, excluding patients with >1 amputation risk that was found to be significant in the multivariate model.

At baseline, 238 patients had a history of amputation.

  • Univariate modelling identified >20 baseline characteristics associated with amputation risk, of which eight remained significant in the multivariate model (male, nonAsian ethnicity, prior amputation, PVD, neuropathy, albuminuria, HbA1c >8%, CANA treatment).
  • Of the 187 patients who experienced a post randomization amputation event, the proximate etiology was as follows:26

Proximate Etiology of Amputation26
CANA
PBO
HR (95% CI)
N/140 (%)
EVRT/1000 PY
N/47 (%)
EVRT/1000 PY
Infection
136 (97)
2.43
47 (100)
1.15
2.18 (1.24-3.83)
Chronic ischemia
82 (59)
3.68
31 (66)
2.22
1.77 (1.17-2.69)
Acute ischemia
2 (1.4)
0.09
0
0.00
-
Undetermined
-
0.14
0
0.00
    • -
Abbreviations: CI, confidence interval; HR, hazard ration; PBO, placebo; PY, patient-year.

At the time of the amputation event: 75% of total patients were on randomized treatment (n=140); 10% were within 30 days after discontinuation of treatment (n=19), and 15% were >30 days after treatment discontinuation (n=28).26

Major Amputation Events in the INVOKANA vs Placebo Groups During the CANVAS Program26

From: Matthews, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019;62(6):926-938. Reprinted with permission from Creative Commons Attribution 4.0.

Minor Amputation Events in the INVOKANA vs Placebo Groups During the CANVAS Program26

From: Matthews, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019;62(6):926-938. Reprinted with permission from Creative Commons Attribution 4.0.

  • The increased risk of amputation with CANA treatment was not linked to any baseline characteristic (P homogeneity >0.123), with a possible exception of antithrombotic treatment, which showed a greater risk in patients on CANA vs. placebo not on antithrombotic treatment (p=0.0268).26
  • The majority of patients experienced a single amputation event (123/187), and the effects of study drug on the risk were comparable to those in patients experiencing >1 amputation event (n=64).26
  • In patients who experienced >1 amputation event in the CANA and placebo groups, 22% vs 19% occurred on the same limb, and 13% vs 17% occurred on both limbs in varying locations, respectively.26
  • Out of 1000 patients treated for 5 years with CANA vs placebo in the CANVAS Program, major amputation events occurred in 4 (95% CI, 1-8) more participants and total amputations (major or minor) occurred in 15 (95% CI, 8-22) more participants.
  • The risk of amputation with CANA vs placebo were lower among subgroups.

Pooled Analysis of CREDENCE Study and CANVAS Program

Barraclough et al (2021)27 conducted a pooled analysis of individual patient data from the CANVAS Program and CREDENCE study to evaluate the cardiovascular and renal outcomes of INVOKANA in patients with T2DM with and without PAD. Safety data in terms of amputation events in patients treated with INVOKANA vs placebo has been described.

  • Overall, 14,543 patients were enrolled (CANVAS Program; n=10,142 and CREDENCE study; n=4401), of whom 3159 (21.7%) had PAD.
  • The rate of amputation events per 1000 PYs in the INVOKANA and placebo groups were 7.53 and 5.62, respectively (HR, 1.50; 95% CI, 1.19-1.89).
    • The rate of amputation events per 1000 PYs in the INVOKANA and placebo groups were 25.21 and 20.02, respectively, for patients with PAD (HR, 1.37; 95% CI, 1.03-1.82) and 3.44 and 2.16, respectively, for patients without PAD (HR, 1.69; 95% CI, 1.122.54) (Pinteraction=0.313).
  • Arnott et al (2020)28 conducted a pooled analysis of patient data from the CANVAS Program and CREDENCE study to determine whether there was an explanation as to why the effects of CANA on amputation risk vary between the studies.
  • Patient characteristics associated with amputation risk were assessed and compared between studies. The main outcome was all atraumatic lower extremity amputations.
  • Baseline amputation history was reported in 2.3% and 5.3% of patients in the CANVAS Program (n=10,142; median follow-up: 2.4 years) and CREDENCE study (n=4401; median follow-up: 2.5 years), respectively. Key differences at baseline included the number of patients with nephropathy (CREDENCE higher, 100% vs 17.5%) and cardiovascular disease (CANVAS higher, 66% vs 50%).
  • There were a total of 133 amputations (CANA, 70; placebo, 63) in CREDENCE (annual event rate: 3.0%) and 187 amputations (CANA, 140; placebo, 47) in CANVAS (annual event rate: 1.8%). Baseline albuminuria and prior amputation were associated with increased amputation risk. The association for both was stronger in the CANVAS program vs. CREDENCE trial (Pheterogeneity=0.04 and 0.01 respectively). Prior amputation was the strongest predictor of future amputation in both studies.
  • Effects of CANA on amputation risk were significantly different between studies (CANVAS Program: HR, 1.97, 95% CI, 1.41-2.75; CREDENCE study: HR, 1.11, 95% CI, 0.79-1.55; Pheterogeneity=0.02; I2=82%); however, this difference was not explained by participant or study differences (Pinteraction values were nonsignificant). In CANVAS, those who were not taking antithrombotics at baseline had a greater risk of amputation than those who were taking antithrombotics (Pinteraction=0.03).
  • In the CANVAS program, both the 100 and 300 mg doses were associated with increased amputation risk. There was no increased risk with the 100 mg dose in CREDENCE.
  • There was no evidence that foot disease management protocols utilized in the CREDENCE study reduced amputation risk.
  • During follow up, there was no statistical difference in amputation risk before 2 years of randomization versus after 2 years (HR, 1.47; 95% CI, 1.12-1.94 and HR, 1.58; 95% CI, 1.00-2.49, respectively, Pinteraction=0.51). This was consistent with the evaluation of each trial separately.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 09 March 2023.

References

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