1 Executive Summary
1.1 Recommendation on Regulatory Action
The CHARM Program was a prospective, randomized clinical trial of the use of candesartan, a selective angiotensin II receptor blocker, in patients with congestive heart failure to decrease cardiovascular morbidity and mortality. The 3 sub studies within the CHARM Program were: CHARM Alternative, CHARM Added, and CHARM Preserved. The focus of this review is CHARM Preserved. Please refer to the review by Dr. Khin U for details on CHARM Alternative and CHARM Added.
CHARM Preserved was a prospective, randomized, double-blind, placebo controlled study to evaluate the effectiveness of candesartan in reducing cardiovascular mortality and/or morbidity in congestive heart failure patients (NYHA Class II through IV) with a preserved ejection fraction (EF > 40%). It is important to note that the choice of an EF > 40% to define a subset of the heart failure population as having “preserved EF” is arbitrary but very relevant to this review. It is possible for patients with an EF around 40% (e.g. 41% to 45% or possibly even higher) to have some degree of systolic dysfunction making them similar to patients in either the CHARM Alternative or CHARM Added study.
In CHARM preserved, an EF > 40% was used as a surrogate to describe heart failure patients as having “diastolic dysfunction.” However, a purist would require evidence of an upward shift in the end-diastolic pressure-volume relation (EDPVR)1,2 to describe such a population. The characterization of the EDPVR is complicated and is not routinely done in clinical practice. The medical literature suggests that CHF patients with an EF > 40% comprise between 20% to 50% of all patients with CHF3. It seems to be widely accepted that patients with diastolic heart failure have a better prognosis compared to patients with systolic heart failure, although recent reports seem to refute this notion4.
The vast majority of research in CHF patients has focused on those with an EF < 40% while the optimal medical management of patients with EF > 40% has yet to be defined. CHARM Preserved represents one of the first attempts to study the effects of a renin angiotensin system blocker in patients with a preserved EF in a prospective, controlled clinical trial.
The CHARM
Preserved study was the sole study submitted by the sponsor to support approval
in patients with a preserved EF. There
were no supportive studies for this indication.
More than 3000 patients with predominantly NYHA Class II and III heart
failure were randomly assigned to placebo or candesartan and followed up for 2
to 4 years. This was a multi-national
study enrolling patients from
Candesartan has been approved for the treatment of hypertension since 1997 and thus has a large post marketing safety experience. Patients in the CHARM Preserved study were followed for a minimum duration of 24 months and a mean duration of 35 months. Study drug discontinuations were higher in the candesartan arm (18%) versus the placebo arm (13%). Three common adverse events of special interest that led to discontinuation of study drug were hyperkalemia, hypotension, and abnormal renal function. Other common AE’s that led to study drug discontinuation were dizziness/vertigo and diarrhea. The frequencies of the adverse events leading to study drug discontinuation were higher on candesartan compared to placebo and were consistent across the entire CHARM Program. Other commonly occurring adverse events that occurred with a greater frequency on candesartan compared to placebo were anemia, dehydration, and fatigue and were consistent across the CHARM Program.
In summary, given the single study that failed to meet its primary endpoint,
of candesartan for use in a subset of heart failure patients with “preserved” EF.
1.2 Recommendation on Postmarketing Actions
N/A
1.3 Summary of Clinical Findings
1.3.1 Brief Overview of Clinical Program
CHARM Preserved was one component of the overall CHARM program that evaluated the efficacy of candesartan to reduce cardiovascular morbidity and mortality in patients with congestive heart failure. CHARM Preserved focused on the subset of patients with an arbitrarily defined EF of greater than 40%. The sponsor provided results from one adequate and well controlled study to support the use of candesartan in this subset population. There were no supportive studies in this subpopulation.
CHARM Preserved was a prospective, randomized, double-blind,
placebo controlled study to evaluate the effectiveness of candesartan in
reducing cardiovascular mortality and CHF hospitalizations in congestive heart
failure patients (NYHA Class II through IV) with a preserved ejection fraction
(EF > 40%).
1.3.2 Efficacy
The CHARM Preserved study was the sole study submitted by
the sponsor to support approval in patients with a preserved EF. There were no supportive studies for this
particular subset of heart failure patients.
More than 3000 patients with predominantly NYHA Class II and III heart
failure were randomly assigned to placebo or candesartan and followed up for 2
to 4 years. The primary endpoint was time
to CV death or CHF hospitalization. The
patients in the two arms of the study were similar at baseline in terms of
demographics and pre-study medications.
The mean age of patients enrolled was 67 years and the mean EF was
54%. More than 1/3 of the patients
enrolled had an EF between 40 and 50.
Approximately 75% of patients were being treated with diuretics at the
time of randomization. The primary
endpoint was reached in 333 patients in the candesartan arm and 366 patients in
the placebo arm: hazard ratio 0.89 (0.77, 1.03), p-value 0.12. CHARM Preserved did not achieve its primary
pre-specified endpoint. Neither
component of the primary endpoint reached a statistically significant p-value of
< 0.05.
1.3.3 Safety
Candesartan has been approved for the treatment of hypertension since 1997 and thus has a large post marketing safety experience. There were no unexpected safety findings from CHARM Preserved. The mean duration in study was 35 months. Study drug discontinuations were higher on candesartan arm versus placebo. Three common adverse events of special interest that led to discontinuation of study drug were hyperkalemia, hypotension, and abnormal renal function. Other common AE’s that led to study drug discontinuation included dizziness/vertigo and diarrhea.
Other commonly occurring adverse events that occurred with a greater frequency on candesartan compared to placebo were anemia, dehydration, and fatigue and were consistent across the CHARM Program.
1.3.4 Dosing Regimen and Administration
Patients randomized to the candesartan arm were started on
daily doses of either 4 or 8 mg and titrated every two weeks to a maximum dose
of 32 mg once daily.
1.3.5 Drug-Drug Interactions
N/A
1.3.6 Special Populations
CHARM Preserved was not designed to evaluate the efficacy of
candesartan as a function of sex or ethnicity.
The effect of candesartan appeared similar in female and male
patients. A subgroup analysis of the
primary endpoint by ethnicity revealed that in Orientals, the effect of
candesartan was negative. The hazard
ratio for cardiovascular mortality and CHF hospitalizations was 3.7 [95%CI (1.2,
12), p-value 0.026.]. A total of 42
Oriental patients contributed 14 primary events. The negative effect of candesartan on the
primary endpoint in the Oriental subgroup seen in CHARM Preserved was consistent
when analyzing pooled data across the entire CHARM Program. In the overall CHARM Program, 133 Oriental
patients contributed 51 primary events.
There is evidence of statistical heterogeneity in this subgroup.
2 Introduction and Background
2.1 Product Information
Candesartan (ATACANDÒ) is a selective
angiotensin II type 1 (AT1) receptor blocker that is currently
approved for the treatment of hypertensive patients. In the current supplemental NDA, the sponsor
has submitted clinical data in support of the use of candesartan in patients
with congestive heart failure.
2.2 Currently Available Treatment for Indications
Nearly all of the guidelines for the management of heart failure are in patients with left ventricular systolic dysfunction (EF < 40%). Currently there are no consensus guidelines for the treatment of heart failure patients with preserved ejection fraction (EF > 40%). Until CHARM Preserved, there have been no studies of adequate size evaluating clinically meaningful endpoints to guide management in the subset of patients with preserved systolic function.
In general terms, management of heart failure patients with
preserved EF (referred to as diastolic heart failure by many) is to reverse the
consequences of diastolic dysfunction (e.g. venous congestion and exercise
intolerance) and secondly to eliminate or reduce factors that are responsible
for diastolic dysfunction (e.g. hypertrophy, fibrosis, ischemia)5. Diuretics are the mainstay of management for
venous congestion while calcium channel blockers are used for their beneficial
effects in terms of myocardial ischemia, hypertension, and/or hypertrophy. However, neither of these two classes of drugs
is labeled for use in patients with diastolic heart failure. Other agents that may also be potentially
beneficial include beta blockers or renin angiotensin system blockers.
2.3
Availability of Proposed Active Ingredient in
the United
States
Candesartan was approved in 1998 for the treatment of
hypertension.
2.4 Important Issues With Pharmacologically Related Products
N/A
2.5 Presubmission Regulatory Activity
Discussed here are key regulatory highlights. Please refer to Dr. Khin U’s review for further details. Table 1 below summarizes major regulatory highlights for this supplemental NDA application.
Table 1: Presubmission Regulatory highlights
|
March 1993 |
Patent issued for candesartan cilexetil |
|
June 1998 |
Candesartan cilexetil approved for the treatment of hypertension |
|
October 1998 |
EOP2 meeting regarding the heart failure program |
|
March 1999 |
The sponsor submitted the CHARM Program (studies SH-AHS-0003, 0006,
and 0007) |
|
November 2003 |
Pre supplemental NDA teleconference between Sponsor and FDA to discuss
plans for filing. |
|
June 2004 |
Supplemental NDA filed |
3 Significant Findings from Other Review Disciplines
3.1 CMC (and Product Microbiology, if Applicable)
No chemistry issues affecting approvability were identified.
3.2 Animal Pharmacology/Toxicology
No animal pharmacology/toxicology issues affecting
approvability were identified.
4 Data Sources, Review Strategy, and Data Integrity
4.1
Sources of Clinical Data
The sponsor submitted one pivotal study (CHARM Preserved)
for the use of candesartan in patients with a preserved ejection fraction. The sponsor’s sNDA submission was in the
electronic CTD format. Case report forms
(CRF’s) for death and study drug discontinuations due to AE’s, case report
tabulations, and clinical study report were provided by the sponsor for
patients in CHARM Preserved.
4.2 Tables of Clinical Studies
The following table lists the one study that was submitted
by the sponsor in support of the use of candesartan in heart failure patients
with preserved EF. Unlike for the other
two components of the CHARM Program, there were no supportive studies conducted
in this subset of patients with heart failure.
Table 2: Table of Clinical Studies in CHARM
Preserved
|
Study |
Title |
|
SH-AHS-0007 (CHARM
Preserved) |
“Clinical Study of
Candesartan in Patients With Heart Failure and Preserved Left Ventricular
Systolic Function” |
4.3 Review Strategy
The focus of this review is CHARM Preserved. The other components of the CHARM Program
(CHARM Alternative and CHARM Added) have been reviewed by Dr. Khin U. I initially read over the original CHARM
protocols and subsequent protocol amendments.
I then read over the sponsor’s clinical study report for CHARM
Preserved. This review is primarily
based on the sponsor’s clinical study report for CHARM Preserved. With the help of the Statistical Reviewer Dr.
Charles Le, the results of the primary efficacy variable were validated. Case report forms for death and study drug
discontinuation due to AE’s were provided.
Selected CRF’s were reviewed in depth.
4.4 Data Quality and Integrity
DSI audits were not felt to be relevant to this efficacy
supplement (Please refer to Dr. Khin U’s review of CHARM Added for a detailed
rationale).
4.5 Compliance with Good Clinical Practices
A debarment certification was signed by a representative of
the sponsor.
4.6 Financial Disclosures
Please refer to Dr. Khin U’s review of CHARM Added for
further details. His review of financial
disclosures is applicable to CHARM Preserved.
5 Clinical Pharmacology
5.1 Pharmacokinetics
Please refer to the detailed “Clinical Pharmacology and Biopharmaceutics Review” completed by Dr. Nhi Beasley.
The pharmacokinetics (PK) of candesartan were studied in
NYHA Class II and III heart failure over the dose range of 2 to 16 mg once
daily. The PK was linear over this dose
range. No attempt was made to examine PK
differences based on low EF or preserved EF and there is no clear rationale of
why such a difference should exist. In
general, the exposure (as measured by plasma concentration area under the
curve) to candesartan was approximately doubled in patients with NYHA Class II
and III heart failure compared to healthy, young patients. As candesartan is not a narrow therapeutic
index drug, this change in exposure is not expected to significantly alter its
safety profile.
5.2 Pharmacodynamics
Please refer to the detailed “Clinical Pharmacology and Biopharmaceutics Review” completed by Dr. Nhi Beasley. No specific pharmacodynamic studies were conducted in patients with preserved EF.
6 Integrated Review of Efficacy
6.1 Indication: Preserved EF
The indication as transcribed from the sponsor’s proposed label is shown below. Highlighted and italicized are sections in the proposed labeling specifically referring to the patient population with a preserved ejection fraction.
“ATACAND is indicated for the treatment of heart
failure (NYHA class II-IV). ATACAND reduces the risk of death from
cardiovascular causes and improves symptoms in patients with left ventricular
systolic dysfunction, and reduces hospitalizations for heart failure
in patients with depressed or preserved
left ventricular systolic function. These
effects occur in patients receiving other heart failure treatments with or
without ACE inhibitors, including patients intolerant to ACE inhibitors, and
with or without beta-blockers.”
In essence the claim the sponsor seeks based on CHARM
Preserved is a reduction in heart failure hospitalizations in patients with a
preserved EF.
6.1.1 Methods
In support of the indication for Preserved EF stated above,
there was one adequate and well controlled trial submitted to NDA 20-863,
SH-AHS-0007, “Clinical Study of Candesartan in Patients With Heart Failure and
Preserved Left Ventricular Systolic Function.”
There were no supportive studies (e.g. Phase 2 studies) submitted for
this indication.
6.1.2 General Discussion of Endpoints
The endpoints collected during this trial were clinically relevant and included both morbidity and mortality. The endpoints chosen in the CHARM program were not inconsistent with endpoints utilized in other large outcome studies involving patients with heart failure. The components of the primary and other secondary endpoints collected during the CHARM program are described below.
Cardiovascular (CV) death: All deaths were considered CV unless an unequivocal non-CV cause could be established. This category included sudden death, death due to MI, death due to heart failure, death due to stroke, death due to a CV investigation/procedure/operation, death due to other CV causes, presumed CV deaths and deaths from unknown causes.
Hospitalization for heart failure: A hospitalization was defined as any overnight stay in a hospital. A CHF hospitalization was defined as admission to hospital necessitated by heart failure and primarily for the treatment of heart failure. A patient admitted for this reason was to demonstrate signs and symptoms of worsening heart failure and require treatment with intravenous diuretics.
Signs or symptoms of worsening heart failure could include at least one of the following:
· Increasing dyspnea on exertion
· Orthopnea
· Nocturnal dyspnea
· Increasing peripheral edema
· Increasing fatigue/decreasing exercise tolerance
· Renal hypoperfusion/ worsening renal function
· Elevated JVP
· Radiologic signs of CHF
All cause mortality: Death from any cause
Myocardial infarction (MI): A diagnosis of MI was to be made if the following conditions were met:
· Creatinine kinase (CK) or CKMB > 2x upper limit of normal (ULN) or
· CK > 3 x ULN immediately following PTCA or
· Troponin I or troponin T > 2 x ULN in hospitals where CK measurement unavailable
AND
· ECG demonstrated development of pathological Q waves and/or the development or disappearance of localized ST-elevations combined with the development of T inversion in at least two of the routine standard leads and clinical history consistent with myocardial infarction.
The CHARM Program utilized a Clinical Endpoints Committee (CEC). The Chair of the Committee was Dr. Scott Solomon. The objectives of the Committee were to classify deaths and to adjudicate CHF hospitalizations and MI’s in a consistent and unbiased manner. The adjudication process was identical for all three components of the CHARM Program. The CEC adjudicated data were used in the analyses of the primary and secondary endpoints. Adjudication was done in a blinded manner. One member of the Committee reviewed each case that was submitted for adjudication. If the CEC member agreed with the principal investigator’s (PI) endpoint diagnosis, the endpoint was considered adjudicated. If the CEC member disagreed with the PI, the endpoint was given to the Chairman for review, discussion, and final adjudication.
6.1.3 Study Design
CHARM Preserved (SH-AHS-0007) was an adequate and well controlled study submitted in support of the use of candesartan in patients with preserved systolic function (EF > 40%.)
CHARM Preserved was a randomized, double-blind, placebo controlled, parallel group, multi-centered study to evaluate the influence of candesartan (4 mg once daily titrated to target dose of 32 mg once daily) on mortality and morbidity endpoints in patients with preserved left ventricular (LV) systolic function.
A pictorial of the study design is shown in Figure 1 below. Following randomization, patients were to have study drug titrated every two weeks as tolerated to a maximum dose of 32 mg once daily.
Figure 1: Study Design of CHARM (SH-AHS-0003, 0006, 0007)
Source: Figure 1 of SH-AHS-0007 CSR
In order to preserve the blind, placebo tablets were identical in appearance to the active drug. The biostatistician of the Safety Committee was the only person that could be unblinded to the data while the CHARM program was in process.
Study randomization was done centrally using an Interactive Voice Response System. Patients were randomized in blocks of four. Patients were randomized to candesartan or placebo in a ratio of 1:1.
As discussed above, the CHARM Program also consisted of a CEC, which adjudicated endpoint events in a blinded manner. In addition, there was also a Data Safety Committee that functioned independently of all other individuals and bodies associated with the conduct of the CHARM Program (e.g. investigators, Steering Committee, and Study Sponsor). The Safety Committee received safety data on a monthly basis and was responsible for reviewing the safety data continually during the program.
A data analysis plan was formulated but not finalized until approximately 2 weeks after study closure.
Placebo was the control treatment in all 3 components of the CHARM program including CHARM Preserved.
The duration of the studies the CHARM Program appeared to be adequate. The patient recruitment period was 16 months. The total study duration could range from 32 to 48 months depending on when a patient was randomized. The minimum duration of patient follow-up post randomization was to be 2 years.
The CHARM Program enrolled patients 18 years of age or older with symptomatic heart failure (NYHA Class II – IV). There were additional study specific inclusion criteria for each component of the CHARM Program. Please refer to section 10.1.1.2 in the Appendix for details regarding inclusion/exclusion criteria.
The current maximum approved dose of candesartan for the
approved indication of hypertension is 32 mg once daily. The CHARM Program was designed as a dose
titration study utilizing maximally tolerated doses of candesartan up to 32
mg.
6.1.4 Efficacy Findings
CHARM Preserved was the lone study in support of the proposed indication in patients with preserved left ventricular systolic function. The study did not achieve its primary pre-specified endpoint of a statistically significant reduction in CV mortality or CHF hospitalizations (p-value of 0.12.)
CHARM Preserved randomized a total of 3025 patients of whom 2 did not receive any study drug. Thus, a total of 3023 patients were evaluable in the ITT population. Three patients in the ITT population were lost to follow-up (2 on placebo, 1 on candesartan). The mean age of study patients was 67 + 11 years. Forty percent of the patients were female, 90% were European, and more than 98% were of Class II/III NYHA class. The etiology of CHF was ischemic heart disease in more than 50% of patients followed by hypertension in approximately 23% of patients. The mean ejection fraction in randomized patients was 54%. The percentage of patients on digitalis glycosides, diuretics, beta-blockers, calcium channel blockers, vasodilators, long acting nitrates, and ACE inhibitors was 28%, 75%, 56%, 69%, 38%, 33%, and 19% respectively.
The baseline characteristics of the two treatment groups were generally similar as shown in Table 28 and Table 29 in the Appendix of this review. Shown in these tables are risk factors for congestive heart failure as well as risk factors for cardiovascular disease for the two treatment groups. The use of various medications at baseline and at study closure are listed in Table 30 located in the Appendix.
The results of the primary efficacy variable are shown below. The results were confirmed independently by Dr. Charles Le, FDA statistician.
Table 3: Efficacy results of primary variable
|
|
Candesartan (N = 1514) |
Placebo (N = 1509) |
Hazard ratio (95% CI) |
p-Value |
|
CV death or CHF hospitalization |
333 |
366 |
0.89 (0.77, 1.03) |
0.12 |
Note: This data in this
table obtained from Table 24 of SH-AHS-0007 CSR
The primary endpoint is displayed graphically in a Kaplan-Meier plot in Figure 2 below.
Figure 2: Cumulative incidence (%) of confirmed adjudicated CV death or hospitalization due to CHF over time
Source: Figure 4 of SH-AHS-0007 CSR
As seen in the table and figure above, the CHARM Preserved study did not meet its primary objective. It is important to note that the incidence of cardiovascular mortality and morbidity was lower in CHARM Preserved compared to the other two components of the CHARM Program as shown in Table 4 below.
Table 4: Comparative event rates in the components of the CHARM Program
|
|
Events per 1000 follow-up years |
|
|
|
Placebo |
Candesartan |
|
SH-AHS-003 (“Alternative”) |
182 |
138 |
|
SH-AHS-006 (“Added”) |
166 |
141 |
|
SH-AHS-0007 (“Preserved”) |
91 |
81 |
Note: Data in this table
obtained from Table 24, Table 23, and Table 23 of SH-AHS-0003, SH-AHS-0006, and
SH-AHS-0007 CSR respectively.
In terms of the individual components contributing to the primary endpoints, there was no statistically significant difference in terms of CV death or in terms of CHF hospitalization as shown in the table below.
Table 5: Components of Primary endpoint
|
|
Candesartan (N = 1514) |
Placebo (N = 1509) |
Hazard ratio (95% CI) |
p-Value |
|
CV death |
170 |
170 |
0.989 (0.80, 1.22) |
0.918 |
|
CHF hospitalization |
241 |
276 |
0.853 (0.718, 1.014) |
0.072 |
Note: The data in this table obtained from Table 30 of SH-AHS-0007 CSR
Various subgroup analyses (e.g. age, sex, and ethnicity) of the primary endpoint are discussed in detail in the Appendix of this review.
The result of one relevant subgroup analysis is shown in Table 6 below.
Table 6: Primary endpoint (CV death, CHF hospitalizations) by baseline EF
|
Variable |
Group |
N |
Cand # of events |
Placebo # of events |
Hazard ratio (95% CI) |
P-value |
|
LVEF |
< 0.50 |
1072 |
106 |
131 |
0.78 (0.60, 1.01) |
0.055 |
|
|
> 0.50 |
1951 |
227 |
235 |
0.95 (0.79, 1.14) |
0.592 |
The tabular results of the secondary endpoints are not
displayed in this review. The pre-specified
secondary endpoint of time from randomization to all cause death and CHF
hospitalization was not statistically significant between the two study
groups. Similarly the other secondary
endpoint consisting of time from randomization to CV death, CHF hospitalization
or non-fatal MI was not statistically significant between the two study
arms.
6.1.5 Efficacy Conclusions
The CHARM Preserved study was the sole study submitted by
the sponsor to support approval in patients with a preserved EF. There were no supportive studies for this
particular subset of heart failure patients.
More than 3000 patients with predominantly NYHA Class II and III heart
failure were randomly assigned to placebo or candesartan and followed up for 2
to 4 years. The primary endpoint was CV
death or CHF hospitalization. The
patients in the two arms of the study were similar at baseline in terms of
demographics and pre-study medications.
The mean EF of patients enrolled was 54%. The primary endpoint was reached in 333
patients in the candesartan arm and 366 patients in the placebo arm: hazard
ratio 0.89 (0.77, 1.03), p-value 0.12.
CHARM Preserved did not achieve its primary pre-specified endpoint.
7 Integrated Review of Safety
7.1 Methods and Findings
The information presented in the safety section of this review was primarily obtained from the sponsor’s clinical study report. Line listings of all patient deaths in the candesartan arm were reviewed. Death narratives of selected cases were also reviewed with referencing of the case report forms.
Table 7 below summarizes the overall AE experience in CHARM preserved. There were nominally more deaths on the candesartan arm compared to the placebo arm during the study period (238 P vs 244 C). The were a greater number of discontinuations due to AE’s and dose reductions due to AE’s in the candesartan arm compared to the placebo arm. A more detailed discussion of these safety findings are provided later in this review.
Table 7: Summary of AE’s, SAE’s, and Discontinuations/dose reductions of study
drug due to AE’s
|
|
Placebo (n =
1509) |
Candesartan
(n =
1514) |
|
Any AE during study |
1060 (70%) |
1074 (71%) |
|
Serious AE’s leading to death during study |
238 (16%) |
244 (16%) |
|
Serious AE’s not leading to death during study |
963 (64%) |
939 (62%) |
|
Discontinuations due to AE’s |
192 (13%) |
269 (18%) |
|
Dose reductions due to AE’s |
125 (8%) |
192 (13%) |
Note: This data in this
table obtained from Table 65 of SH-AHS-0007 CSR
7.1.1 Deaths
There were a total of 482 deaths during the study of which 238 occurred in patients randomized to placebo and 244 in patients randomized to candesartan. Table 8 shows the most common AE’s leading to death. The etiologies of death in the two treatment arms were similar. The most common etiologies of death were not unexpected given the patient population enrolled into the study. The most common etiologies of death in CHARM Preserved were similar to the etiologies in the overall CHARM Program and were mainly cardiovascular in nature (e.g. sudden death, heart failure, myocardial infarction). Line listings of all deaths, located in the sponsor’s clinical study report SH-AHS-0007, Appendix 12.2.7.2, that included the sponsors “Preferred Term” and the investigator’s terms were reviewed. In general, the sponsor’s coding of adverse events based on the investigator’s verbatim term was acceptable. Line listings from all deaths in the candesartan arm were reviewed. Narratives of death from selected cases and their respective case report forms (CRF’s) were also reviewed.
Table 8: AE’s leading to death in CHARM preserved (cutoff > 0.3%)
|
|
Placebo |
Cand |
||||
|
Preferred term |
(N=1509) |
|
(N=1514) |
|
||
|
|
N |
(%) |
N |
(%) |
||
|
Sudden death |
68 |
(4.5) |
68 |
(4.5) |
||
|
Cardiac failure/cardiac |
|
|
|
|
||
|
failure aggravatedb |
53 |
(3.5) |
41 |
(2.7) |
||
|
Myocardial infarction |
20 |
(1.3) |
18 |
(1.2) |
||
|
Pneumonia |
19 |
(1.3) |
14 |
(0.9) |
||
|
Cerebrovascular disorder |
14 |
(0.9) |
11 |
(0.7) |
||
|
Death |
11 |
(0.7) |
7 |
(0.5) |
||
|
Sepsis |
9 |
(0.6) |
6 |
(0.4) |
||
|
Respiratory insufficiency |
8 |
(0.5) |
5 |
(0.3) |
||
|
Pulmonary oedema |
6 |
(0.4) |
6 |
(0.4) |
||
|
Renal failure acute |
6 |
(0.4) |
5 |
(0.3) |
||
|
Accident and/or injury |
6 |
(0.4) |
4 |
(0.3) |
||
|
Pulmonary carcinoma |
5 |
(0.3) |
5 |
(0.3) |
||
|
Renal failure nos |
4 |
(0.3) |
5 |
(0.3) |
||
|
Coronary artery disorder |
5 |
(0.3) |
3 |
(0.2) |
||
Note: This data in this
table obtained from Table 67 of SH-AHS-0007 CSR
7.1.2 Other Serious Adverse Events
Table 9 below lists serious adverse events (SAE’s) other than death that occurred on treatment in CHARM preserved. The table lists SAE’s occurring at a frequency of at least 1% based on the candesartan arm. The 4 most common serious adverse events not leading to death on the candesartan arm were cardiac failure, angina pectoris, atrial fibrillation, and pneumonia. In general the frequency of these SAE’s was similar or lower to that observed in the placebo arm.
Adverse events that occurred with frequency that was nominally higher on candesartan compared to placebo included hypotension, anemia, syncope, renal failure (acute), GI hemorrhage, renal function abnormal, skin cellulitis, bradycardia, renal failure NOS, dehydration, respiratory infection, diarrhea, ventricular tachycardia/arrhythmias, atrial flutter, hyperkalemia, arteriosclerosis, AV block, hernia, and fracture. Of these listed AE’s, three occurred with a frequency that was 2 fold higher on candesartan compared to placebo and are highlighted in the table below. These include dehydration, hyperkalemia, and fracture.
Three adverse events of special interest, hypotension, hyperkalemia, and renal dysfunction/renal failure occurred more frequently on candesartan compared to placebo. The adverse events of hypotension and hyperkalemia were notably higher in the candesartan arm compared to the placebo arm: hypotension (4.9% vs. 3.6%), hyperkalemia (1.5% vs. 0.4%). The adverse events of “renal failure acute”, “renal function abnormal/renal dysfunction aggravated”, and “renal failure NOS” occurred with a higher incidence on candesartan compared to placebo.
Another SAE worth noting that occurred with a greater frequency on candesartan compared to placebo was anemia. There is more discussion of this AE later in this review.
Table
9: Serious Adverse Events other than Death
(Frequency > 1% on candesartan)
|
|
Placebo
on |
Cand
on |
||
|
Preferred term |
Treatment |
Treatment |
||
|
|
(n=1509) |
(n=1514) |
||
|
|
n |
(%) |
N |
(%) |
|
Cardiac failure/cardiac |
|
|
|
|
|
failure aggravated |
303 |
(20.1) |
234 |
(15.5) |
|
Angina pectoris/angina |
|
|
|
|
|
pectoris aggravated |
195 |
(12.9) |
179 |
(11.8) |
|
Fibrillation atrial |
103 |
(6.8) |
77 |
(5.1) |
|
Pneumonia |
81 |
(5.4) |
76 |
(5.0) |
|
Coronary artery disorder |
85 |
(5.6) |
69 |
(4.6) |
|
Cerebrovascular disorder |
83 |
(5.5) |
65 |
(4.3) |
|
Myocardial infarction |
74 |
(4.9) |
63 |
(4.2) |
|
Chest pain |
69 |
(4.6) |
66 |
(4.4) |
|
Tachycardia supraventricular |
76 |
(5.0) |
55 |
(3.6) |
|
Arrhythmia atrial |
73 |
(4.8) |
53 |
(3.5) |
|
Hypotension |
54 |
(3.6) |
74 |
(4.9) |
|
Accident and/or injury |
46 |
(3.0) |
45 |
(3.0) |
|
Anaemia |
35 |
(2.3) |
45 |
(3.0) |
|
Syncope |
32 |
(2.1) |
43 |
(2.8) |
|
Dyspnoea/dyspnea |
|
|
|
|
|
(aggravated) |
39 |
(2.6) |
24 |
(1.6) |
|
Arrhythmia ventricular |
36 |
(2.4) |
23 |
(1.5) |
|
Diabetes mellitus/diabetes |
|
|
|
|
|
mellitus aggravated |
30 |
(2.0) |
26 |
(1.7) |
|
Renal failure acute |
24 |
(1.6) |
30 |
(2.0) |
|
Gi haemorrhage |
20 |
(1.3) |
25 |
(1.7) |
|
Bronchitis/bronchitis |
|
|
|
|
|
aggravated |
25 |
(1.7) |
24 |
(1.6) |
|
Chronic obstruct airways |
|
|
|
|
|
Disease |
27 |
(1.8) |
23 |
(1.5) |
|
Pulmonary oedema |
26 |
(1.7) |
21 |
(1.4) |
|
Renal function |
|
|
|
|
|
abnormal/renal dysfunction |
|
|
|
|
|
aggravated |
18 |
(1.2) |
28 |
(1.8) |
|
Cellulitis skin |
20 |
(1.3) |
24 |
(1.6) |
|
Dizziness/vertigo |
24 |
(1.6) |
23 |
(1.5) |
|
Hypertension |
32 |
(2.1) |
12 |
(0.8) |
|
Bradycardia |
16 |
(1.1) |
25 |
(1.7) |
|
Renal failure nos |
14 |
(0.9) |
23 |
(1.5) |
|
Urinary tract infection |
18 |
(1.2) |
18 |
(1.2) |
|
Arthrosis |
21 |
(1.4) |
19 |
(1.3) |
|
Dehydration |
10 |
(0.7) |
25 |
(1.7) |
|
Respiratory infection |
16 |
(1.1) |
20 |
(1.3) |
|
Diarrhoea |
15 |
(1.0) |
20 |
(1.3) |
|
Tachycardia |
|
|
|
|
|
ventricular/arrhythmia |
14 |
(0.9) |
19 |
(1.3) |
|
Atrial flutter |
13 |
(0.9) |
17 |
(1.1) |
|
Sick sinus syndrome |
16 |
(1.1) |
17 |
(1.1) |
|
Hyperkalaemia |
6 |
(0.4) |
22 |
(1.5) |
|
Arteriosclerosis |
10 |
(0.7) |
17 |
(1.1) |
|
Av block |
12 |
(0.8) |
16 |
(1.1) |
|
Hernia |
11 |
(0.7) |
17 |
(1.1) |
|
Fracture |
9 |
(0.6) |
18 |
(1.2) |
Taken from Table 129 of
SH-AHS-0007 CSR
7.1.3 Dropouts and Other Significant Adverse Events
Dropouts due to AE’s and dose reductions due to AE’s were
greater on the candesartan arm compared to the placebo arm in CHARM
Preserved. This pattern was observed in
all 3 components of the CHARM Program.
More details are provided below.
7.1.3.1 Adverse events associated with dropouts
As shown earlier, the study drug was permanently discontinued due to AE’s in 192 patients randomized to placebo and 269 patients randomized to candesartan. As shown in Table 10 below, AE’s leading to study drug discontinuation that were at least twice as common on candesartan compared to placebo were abnormal renal function, hypotension, hyperkalemia, dizziness/vertigo, renal failure, diarrhea, and nausea. The sponsor’s coding of adverse events based on the investigator’s verbatim terms were acceptable.
Table 10: Summary of discontinuations due to AE’s in CHARMED preserved (cutoff > 0.5%)
|
Preferred term |
Placebo |
Cand |
||
|
|
(N=1509) |
|
(N=1514) |
|
|
|
N |
(%) |
N |
(%) |
|
Renal function abnormal |
32 |
(2.1) |
68 |
(4.5) |
|
Cardiac failure/cardiac failure
aggravated |
33 |
(2.2) |
43 |
(2.8) |
|
Hypotension |
18 |
(1.2) |
40 |
(2.6) |
|
Hyperkalaemia |
8 |
(0.5) |
23 |
(1.5) |
|
Cerebrovascular disorder |
11 |
(0.7) |
14 |
(0.9) |
|
Angina pectoris |
7 |
(0.5) |
12 |
(0.8) |
|
Myocardial infarction |
13 |
(0.9) |
6 |
(0.4) |
|
Dizziness/vertigo |
4 |
(0.3) |
14 |
(0.9) |
|
Renal failure nos |
4 |
(0.3) |
12 |
(0.8) |
|
Diarrhoea |
3 |
(0.2) |
11 |
(0.7) |
|
Dyspnoea/dyspnoea (aggravated) |
6 |
(0.4) |
8 |
(0.5) |
|
Nausea |
4 |
(0.3) |
10 |
(0.7) |
|
Pneumonia |
8 |
(0.5) |
6 |
(0.4) |
Note: This data in this
table obtained from Table 69 of SH-AHS-0007 CSR
Table 11 below summarizes the reductions in dosages of study drugs due to adverse events. Several of the findings in this table are consistent with those in Table 10. AE’s leading to a reduction in study drug dose that were at least twice as common on candesartan compared to placebo were hypotension and hyperkalemia. The frequency of abnormal renal function was also higher in patients randomized to candesartan compared to placebo but just missed the two fold threshold. Fatigue was also a reason for reduction in study drug dose that was twice as frequent on candesartan relative to placebo.
Table 11: Summary of dose reductions due to AE’s in CHARMED preserved (cutoff > 0.3%)
|
Preferred term |
Placebo |
Cand |
||
|
|
(N=1509) |
|
(N=1514) |
|
|
|
N |
(%) |
N |
(%) |
|
Hypotension |
52 |
(3.4) |
106 |
(7.0) |
|
Renal function abnormal |
17 |
(1.1) |
30 |
(2.0) |
|
Dizziness/vertigo |
21 |
(1.4) |
16 |
(1.1) |
|
Hyperkalaemia |
5 |
(0.3) |
16 |
(1.1) |
|
Fatigue |
5 |
(0.3) |
12 |
(0.8) |
|
Cardiac failure aggravated |
13 |
(0.9) |
10 |
(0.7) |
|
Nausea |
5 |
(0.3) |
6 |
(0.4) |
|
Dyspnoea/dyspnoea (aggravated) |
6 |
(0.4) |
5 |
(0.3) |
|
Asthenia |
3 |
(0.2) |
5 |
(0.3) |
Note: This data in this
table obtained from Table 70 of SH-AHS-0007 CSR
7.1.4 Common Adverse Events
Common AE’s causing study drug discontinuation or down-titration were recorded in the CRF. Non-serious AE’s that did not lead to drug discontinuation or dose reduction were not recorded. Assessments for AE’s were made during the up titration period and every 4 months until the end of the study as shown in Figure 5 in the Appendix.
7.1.4.1 Common adverse event tables
The table below lists AE’s occurring with a frequency of > 1% in the candesartan arm on treatment and the corresponding frequency on the placebo comparator.
Three adverse events that are worth noting and that occurred with a significantly higher frequency on candesartan compared to placebo were hypotension, abnormal renal function, and hyperkalemia. These AE’s have also been discussed in a previous section dealing with discontinuation/dose reduction due to AE’s. These AE’s occurred at a consistently higher frequency on candesartan compared to placebo for the entire CHARM Program.
Other AE’s that occurred more frequently on candesartan compared to placebo and were consistent across the CHARM Program included dizziness/vertigo, syncope, diarrhea, fatigue, and anemia.
Table 12: Common AE’s occurring in CHARM Preserved
(AE’s
with a frequency > 1% in the candesartan arm)
|
|
Placebo on |
Cand. cil. on |
||
|
Preferred term |
treatment |
treatment |
||
|
|
(N=1509) |
(N=1514) |
||
|
|
N |
(%) |
N |
(%) |
|
Cardiac failure/cardiac failure |
|
|
|
|
|
aggravatedb |
321 |
(21.3) |
247 |
(16.3) |
|
Angina pectoris/angina |
|
|
| |