Scolaris Content Display Scolaris Content Display

Study flow diagram.
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Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 1 All‐cause mortality.
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Analysis 1.1

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 1 All‐cause mortality.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 2 Cardiovascular mortality.
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Analysis 1.2

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 2 Cardiovascular mortality.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 3 Parathyroidectomy.
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Analysis 1.3

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 3 Parathyroidectomy.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 4 Fractures.
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Analysis 1.4

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 4 Fractures.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 5 Hypocalcaemia.
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Analysis 1.5

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 5 Hypocalcaemia.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 6 Hypercalcaemia.
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Analysis 1.6

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 6 Hypercalcaemia.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 7 Nausea.
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Analysis 1.7

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 7 Nausea.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 8 Vomiting.
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Analysis 1.8

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 8 Vomiting.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 9 Diarrhoea.
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Analysis 1.9

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 9 Diarrhoea.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 10 Abdominal pain.
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Analysis 1.10

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 10 Abdominal pain.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 11 Upper respiratory tract infection.
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Analysis 1.11

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 11 Upper respiratory tract infection.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 12 Asthenia, muscle weakness or paraesthesia.
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Analysis 1.12

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 12 Asthenia, muscle weakness or paraesthesia.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 13 Dyspnoea.
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Analysis 1.13

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 13 Dyspnoea.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 14 Headache.
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Analysis 1.14

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 14 Headache.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 15 Achievement of PTH target.
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Analysis 1.15

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 15 Achievement of PTH target.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 16 PTH.
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Analysis 1.16

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 16 PTH.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 17 Serum calcium.
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Analysis 1.17

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 17 Serum calcium.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 18 Serum phosphorous.
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Analysis 1.18

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 18 Serum phosphorous.

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 19 Calcium x phosphorous.
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Analysis 1.19

Comparison 1 Calcimimetics versus placebo/no treatment, Outcome 19 Calcium x phosphorous.

Summary of findings for the main comparison. Summary of findings for dialysis patients

Cinacalcet plus standard therapy versus placebo or standard therapy or both for patients with CKD and elevated PTH levels

Patient or population: adults with CKD

Outcomes

(median treatment duration)

*Best estimate of control group risk

Relative effect
(95% CI)

No of participants
(studies)

Absolute effect per one year of treatment for 1000 treated (95%CI)

Quality of the evidence
(GRADE)

GFR category G5 treated with dialysis

All‐cause mortality

(8 months)

200 per 1000

RR 0.97 (0.89 to 95)

6893 (14)

6 fewer (22 fewer to 10 more)

⊕⊕⊕⊕
high

Parathyroidectomy

(9 months)

7 per 1000

RR 0.49 (0.40 to 0.59)

4893 (5)

3 fewer (4 fewer to 3 fewer)

⊕⊕⊕⊕
high

Hypocalcaemia

(7 months)

10 per 1000

RR 6.98 (5.10 to 9.53)

6415 (12)

60 more (41 more to 85 more)

⊕⊕⊕⊕
high

Nausea

(7 months)

150 per 1000

RR 2.02 (1.45 to 2.81)

6450 (12)

153 more (68 more to 272 more)

⊕⊕⊕
moderate

GFR category G3a‐G4

All‐cause mortality

(8 months)

25 per 1000

RR 0.29 (0.06 to 1.48)

458 (2)

18 fewer (23 fewer to 12 more)

⊕⊕
low

Parathyroidectomy

(9 months)

7 per 1000

RR not estimable

0 (0)

Not estimable

nil

Hypocalcaemia

(7 months)

10 per 1000

RR 31.9 (5.28 to 192.6)

449 (2)

310 more (43 more to 1910 more)


very low

Nausea

(7 months)

100 per 1000

RR 2.26 (1.29 to 3.95)

449 (2)

126 more (29 more to 295 more)

⊕⊕

low

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio;

Approximate absolute event rates of outcomes per year are derived from previously published cohort studies and registry data for the outcomes of all‐cause mortality (Weiner 2006) and parathyroidectomy (Kestenbaum 2004) or event rates in the control arm of contributing studies for outcomes of hypocalcaemia and nausea. Absolute numbers of people who had chronic kidney disease with mortality or parathyroidectomy events avoided or nausea or hypocalcaemia events caused per 1000 treated were calculated from the risk estimate for the outcome (and associated 95% confidence interval) obtained from meta‐analysis of placebo‐controlled studies together with the absolute population risk estimates.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

CKD ‐ chronic kidney disease; GFR ‐ glomerular filtration rate; PTH‐ parathyroid hormone

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Summary of findings for the main comparison. Summary of findings for dialysis patients
Table 1. Current chronic kidney disease nomenclature used by KDIGO nomenclature

Prognosis of CKD by GFR and albuminuria categories: KDIGO 2012

Persistent albuminuria categories

Description and range

A1

Normal to

mildly

increased

A2

Moderately

increased

A3

Severely

increased

< 30 mg/g

< 3 mg/mmol

30 to 300 mg/g

3 to 30 mg/mmol

> 300 mg/g

> 30 mg/mmol

GFR categories

(mL/min per 1.73 m²)

Description and range

G1

G2

Normal or high

Mildly decreased

> 90

60 to 89

Low

Moderate

High

G3a

Mild to moderately decreased

45 to 59

Moderate

High

Very high

G3b

Moderate to severely decreased

30 to 44

High

Very high

G4

Severely decreased

15 to 29

Very high

G5

Kidney failure

< 15

Description of the Kidney Disease: Improving Global Outcomes (KDIGO) nomenclature for chronic kidney disease used in this review (see the full KDIGO CKD 2013 for additional information).

GFR ‐ glomerular filtration rate

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Table 1. Current chronic kidney disease nomenclature used by KDIGO nomenclature
Table 2. Definitions of parathyroid hormone target, and hypercalcaemia and hypocalcaemia endpoints

Study

Participants (treatment/control)

PTH level triggering reduction in cinacalcet dose

Calcium level triggering reduction in cinacalcet dose

Hypocalcaemia (study endpoint)

Hypercalcaemia (study endpoint)

ACHIEVE Study 2008

173 (87/86)

< 150 pg/mL

Symptoms of hypocalcaemia or < 7.5 mg/dL

< 8.4 mg/dL

> 10.2 mg/dL

ADVANCE Study 2010

360 (180/180)

‐‐

‐‐

Hypocalcaemia

Hypercalcaemia

Akiba 2008

121 (91/30)

‐‐

‐‐

Hypocalcaemia

‐‐

Block 2004a

741 (371/370)

< 100 pg/mL

Symptoms of hypocalcaemia or < 7.8 mg/dL

Withdrawal due to hypocalcaemia

‐‐

Charytan 2005

54 (27/27)

‐‐

Dose‐related adverse event or < 7.8 mg/dL

< 8.4 mg/dL

‐‐

Chonchol 2009

404 (302/102)

PTH < 35 pg/mL for stage 3 and < 70 pg/mL for stage 4

Symptoms of hypocalcaemia or < 7.5 mg/dL

< 7.5 mg/dL

‐‐

El Shafey 2011

82 (55/27)

< 92 pg/mL

Dose‐related adverse event or < 7.5 mg/dL

Hypocalcaemia

‐‐

EVOLVE study 2007

3883 (1948/1935)

< 150 pg/mL

< 7.5 mg/dL and/or symptoms of hypocalcaemia

< 8.0 mg/dL or < 7.5 mg/dL (unclear which threshold reported in study)

> 10.5 mg/dL

Fukagawa 2008

145 (72/73)

Investigators’ discretion or excessive decrease in PTH level

Investigators’ discretion or < 7.5 mg/dL

Hypocalcaemia

‐‐

Goodman 2000

21 (16/5)

‐‐

Symptoms of hypocalcaemia or ionised calcium < 4 mg/dL

Ionized calcium < 4 mg/dL

‐‐

Goodman 2002

30 (23/7)

‐‐

8.0 mg/dL

< 8.0 mg/dL

‐‐

Harris 2004

23 (17/6)

‐‐

‐‐

‐‐

‐‐

IMPACT SHPT Study 2012

264 (134/134)

< 150 pg/mL

< 7.5 mg/dL

<8,.4 mg/dL

> 10.5 mg/dL

Lindberg 2003

78 (39/39)

< 100 pg/mL

Symptoms of hypocalcaemia or < 7.8 mg/dL

< 7.5 mg/dL

‐‐

Lindberg 2005

395 (294/101)

‐‐

Symptoms of hypocalcaemia or < 7.8 mg/dL

‐‐

‐‐

Malluche 2008

32 (19/13)

< 100 pg/mL

Symptoms of hypocalcaemia or < 7.8 mg/dL

‐‐

‐‐

OPTIMA Study 2008

552 (368/184)

< 150 pg/mL

< 8.0 mg/dL

< 7.5 mg/dL

‐‐

Quarles 2003a

71 (36/35)

< 100 pg/mL

< 7.8 mg/dL

‐‐

‐‐

PTH ‐ parathyroid hormone

Figures and Tables -
Table 2. Definitions of parathyroid hormone target, and hypercalcaemia and hypocalcaemia endpoints
Comparison 1. Calcimimetics versus placebo/no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

16

7351

Risk Ratio (IV, Random, 95% CI)

0.96 [0.89, 1.05]

1.1 GFR category G5 treated with dialysis

14

6893

Risk Ratio (IV, Random, 95% CI)

0.97 [0.89, 1.05]

1.2 GFR category G3a to G4

2

458

Risk Ratio (IV, Random, 95% CI)

0.29 [0.06, 1.48]

2 Cardiovascular mortality Show forest plot

9

5000

Risk Ratio (IV, Random, 95% CI)

0.68 [0.32, 1.45]

2.1 GFR category G5 treated with dialysis

7

4542

Risk Ratio (IV, Random, 95% CI)

0.67 [0.16, 2.87]

2.2 GFR category G3a to G4

2

458

Risk Ratio (IV, Random, 95% CI)

0.29 [0.06, 1.48]

3 Parathyroidectomy Show forest plot

5

4893

Risk Ratio (IV, Random, 95% CI)

0.49 [0.40, 0.59]

4 Fractures Show forest plot

2

3965

Risk Ratio (IV, Random, 95% CI)

0.52 [0.12, 2.27]

5 Hypocalcaemia Show forest plot

14

6864

Risk Ratio (IV, Random, 95% CI)

7.38 [5.43, 10.03]

5.1 GFR category G5 treated with dialysis

12

6415

Risk Ratio (IV, Random, 95% CI)

6.98 [5.10, 9.53]

5.2 GFR category G3a to G4

2

449

Risk Ratio (IV, Random, 95% CI)

31.90 [5.28, 192.60]

6 Hypercalcaemia Show forest plot

4

4662

Risk Ratio (IV, Random, 95% CI)

0.23 [0.05, 0.97]

7 Nausea Show forest plot

14

6899

Risk Ratio (IV, Random, 95% CI)

2.05 [1.54, 2.75]

7.1 GFR category G5 treated with dialysis

12

6450

Risk Ratio (IV, Random, 95% CI)

2.02 [1.45, 2.81]

7.2 GFR category G3a to G4

2

449

Risk Ratio (IV, Random, 95% CI)

2.26 [1.29, 3.95]

8 Vomiting Show forest plot

10

6718

Risk Ratio (IV, Random, 95% CI)

1.95 [1.74, 2.18]

8.1 GFR category G5 treated with dialysis

9

6323

Risk Ratio (IV, Random, 95% CI)

1.97 [1.73, 2.24]

8.2 GFR category G3a to G4

1

395

Risk Ratio (IV, Random, 95% CI)

1.77 [0.90, 3.48]

9 Diarrhoea Show forest plot

8

5639

Risk Ratio (IV, Random, 95% CI)

1.15 [1.02, 1.29]

10 Abdominal pain Show forest plot

4

831

Risk Ratio (IV, Random, 95% CI)

1.62 [0.55, 4.82]

11 Upper respiratory tract infection Show forest plot

4

1856

Risk Ratio (IV, Random, 95% CI)

0.95 [0.39, 2.33]

12 Asthenia, muscle weakness or paraesthesia Show forest plot

5

1379

Risk Ratio (IV, Random, 95% CI)

1.55 [0.93, 2.58]

12.1 Asthenia

2

790

Risk Ratio (IV, Random, 95% CI)

1.54 [0.26, 8.98]

12.2 Muscle weakness or paraesthesia

4

589

Risk Ratio (IV, Random, 95% CI)

1.78 [1.00, 3.14]

13 Dyspnoea Show forest plot

2

250

Risk Ratio (IV, Random, 95% CI)

1.02 [0.49, 2.12]

14 Headache Show forest plot

3

1115

Risk Ratio (IV, Random, 95% CI)

1.11 [0.65, 1.91]

15 Achievement of PTH target Show forest plot

11

2853

Risk Ratio (IV, Random, 95% CI)

3.06 [1.89, 4.98]

16 PTH Show forest plot

7

1935

Mean Difference (IV, Random, 95% CI)

‐280.39 [‐325.84, ‐234.94]

17 Serum calcium Show forest plot

7

1556

Mean Difference (IV, Random, 95% CI)

‐0.87 [‐0.96, ‐0.77]

18 Serum phosphorous Show forest plot

8

2300

Mean Difference (IV, Random, 95% CI)

‐0.23 [‐0.58, 0.12]

19 Calcium x phosphorous Show forest plot

8

2395

Mean Difference (IV, Random, 95% CI)

‐5.25 [‐9.16, ‐1.34]

Figures and Tables -
Comparison 1. Calcimimetics versus placebo/no treatment