Funnel plot: lipoprotein(a). Physique?S32. angina. Physique?S21. Funnel plot: congestive heart failure exacerbation. Physique?S22. Funnel plot: neurocognitive adverse events. Physique?S23. Funnel plot: diabetes mellitus. Physique?S24. Funnel plot: increase in creatine kinase. Physique?S25. Funnel plot: myalgia. Physique?S26. Funnel plot: increase in alanine or aspartate aminotransferase. Physique?S27. Funnel plot: treatment\emergent severe adverse events. Physique?S28. Funnel plot: low\density lipoprotein cholesterol. Physique?S29. Funnel plot: high\density lipoprotein cholesterol. Physique?S30. Funnel plot: total cholesterol. Physique?S31. Funnel plot: lipoprotein(a). Physique?S32. Funnel plot: apolipoprotein B. JAH3-6-e006910-s001.pdf (2.2M) GUID:?B76D4795-19CD-4743-BE4C-6B8263DB6790 Abstract Background We sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab. Methods and Results We performed a systematic review and meta\analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45?539 patients (mean follow\up: 85.5?weeks) were included. Mean age was 61.02.8?years, and mean baseline low\density lipoprotein cholesterol was 10622?mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64C0.81]; value of <0.05 was considered statistically significant. All analyses were performed using Review Manager version 5.3 (RevMan; Cochrane Collaboration) and Comprehensive Meta\Analysis Software version 3.3 (Biostat, Inc). Results Study Selection and Patient Populace The PRISMA study identification flowchart for the present analysis is usually shown in Physique?S1. A total of 138 study arms from 35 studies were analyzed, comprising 45?539 patients (Table?S1).5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Alirocumab was used in 18 studies (28 treatment arms), and evolocumab was used in 17 studies (39 treatment arms; Physique?1); placebo was the most common control used (52 control arms), with ezetimibe used in 17 arms, and standard therapy in 2 arms. Eight studies were of an exclusively FH populace, and 5 studies included only patients intolerant to statins. Mean treatment period in the randomized populace up to the time of reporting was 85.5?weeks (range: 8C113?weeks). Open in a separate windows Physique 1 Timeline of randomized controlled trials of alirocumab and evolocumab. FDA indicates US Food and Drug Administration; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia. Baseline individual characteristics for the study arms included are shown in Table?S2. Mean age was 61.02.8?years, and 67.6% of participants were men; the imply baseline LDL\C was 106.022.3?mg/dL (2.70.6?mmol/L). The majority of study participants (91.8%) were on stable statin therapy at baseline, and 58.4% were on an intensive statin regimen. From 45?539 total patients in the randomized population, safety data were available and abstracted for 45?503 (99.9%). Risk of methodological bias was assessed as low in most studies (Physique?S2). All\Cause Mortality Thirty\five RCTs (45?503 participants) were included in the analysis of all\cause mortality (Figure?2). Compared with no treatment with a PCSK9 inhibitor, treatment with a PCSK9 inhibitor was not associated with a statistically significant change in mortality (crude rate, 1.9% versus 2.2%; OR: 0.71 [95% CI, 0.47C1.09]; P=0.12, I2=18%, heterogeneity P=0.26). Random effects metaregression showed a significant association between baseline LDL\C and all\cause mortality benefit (P=0.038; Figure?3). Open in a separate window Figure 2 All\cause mortality. Forrest plot showing the odds ratio for all\cause mortality with PCSK9 (proprotein convertase.Apolipoprotein B percentage of change from baseline. Figure?S15. change from baseline. Figure?S12. Total cholesterol percentage of change from baseline. Figure?S13. Lipoprotein(a) percentage of change from baseline. Figure?S14. Apolipoprotein B percentage of change from baseline. Figure?S15. Funnel plot: all\cause mortality. Figure?S16. Funnel plot: cardiovascular mortality. Figure?S17. Funnel plot: myocardial infarction. Figure?S18. Funnel plot: stroke. Figure?S19. Funnel plot: coronary revascularization. Figure?S20. Funnel plot: unstable angina. Figure?S21. Funnel plot: congestive heart failure exacerbation. Figure?S22. Funnel plot: neurocognitive adverse events. Figure?S23. Funnel plot: diabetes mellitus. Figure?S24. Funnel plot: increase in creatine kinase. Figure?S25. Funnel plot: myalgia. Figure?S26. Funnel plot: increase in alanine or aspartate aminotransferase. Figure?S27. Funnel plot: treatment\emergent serious adverse events. Figure?S28. Funnel plot: low\density lipoprotein cholesterol. Figure?S29. Funnel plot: high\density lipoprotein cholesterol. Figure?S30. Funnel plot: total cholesterol. Figure?S31. Funnel plot: lipoprotein(a). Figure?S32. Funnel plot: apolipoprotein B. JAH3-6-e006910-s001.pdf (2.2M) GUID:?B76D4795-19CD-4743-BE4C-6B8263DB6790 Abstract Background We sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab. Methods and Results We performed a systematic review and meta\analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45?539 patients (mean follow\up: 85.5?weeks) were included. Mean age was 61.02.8?years, and mean baseline low\density lipoprotein cholesterol was 10622?mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64C0.81]; value of <0.05 was considered statistically significant. All analyses were performed using Review Manager version 5.3 (RevMan; Cochrane Collaboration) and Comprehensive Meta\Analysis Software version 3.3 (Biostat, Inc). Results Study Selection and Patient Human population The PRISMA study recognition flowchart for the present analysis is demonstrated in Number?S1. A total of 138 study arms from 35 studies were analyzed, comprising 45?539 individuals (Table?S1).5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Alirocumab was used in 18 studies (28 treatment arms), and evolocumab was used in 17 studies (39 treatment arms; Number?1); placebo was the most common control used (52 control arms), with ezetimibe used in 17 arms, and standard therapy in 2 arms. Eight studies were of an exclusively FH human population, and 5 studies included only individuals intolerant to statins. Mean treatment o-Cresol period in the randomized human population up to the time of reporting was 85.5?weeks (range: 8C113?weeks). Open in a separate window Number 1 Timeline of randomized controlled tests of alirocumab and evolocumab. FDA shows US Food and Drug Administration; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia. Baseline individual characteristics for the study arms included are demonstrated in Table?S2. Mean age was 61.02.8?years, and 67.6% of participants were men; the imply baseline LDL\C was 106.022.3?mg/dL (2.70.6?mmol/L). The majority of study participants (91.8%) were on stable statin therapy at baseline, and 58.4% were on an intensive statin routine. From 45?539 total patients in the randomized population, safety data were available and abstracted for 45?503 (99.9%). Risk of methodological bias was assessed as low in most studies (Number?S2). All\Cause Mortality Thirty\five RCTs (45?503 participants) were included in the analysis of most\cause mortality (Number?2). Compared with no treatment having a PCSK9 inhibitor, treatment having a PCSK9 inhibitor was not associated with a statistically significant switch in mortality (crude rate, 1.9% versus 2.2%; OR: 0.71 [95% CI, 0.47C1.09]; P=0.12, I2=18%, heterogeneity P=0.26). Random effects metaregression showed a significant association between baseline LDL\C and all\cause mortality benefit (P=0.038; Number?3). Open in a separate window Number 2 All\cause mortality. Forrest storyline showing the odds percentage for all\cause mortality with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was determined with random effects according to the Mantel\Haenszel (M\H) method. Marker size is definitely proportional to the study excess weight. CI indicates confidence interval. Open up in another window Body 3 Research\level metaregression evaluation with random results showing the partnership between baseline low\thickness lipoprotein cholesterol (LDL\C) and all\trigger mortality. Group size is proportional towards the scholarly research fat; 95% self-confidence intervals proven in blue. Cardiovascular Mortality Thirty\four RCTs (44?701 individuals) were contained in the evaluation of cardiovascular mortality (Body?4). Weighed against no treatment using a PCSK9 inhibitor, treatment using a PCSK9 inhibitor had not been associated with a substantial transformation in statistically.Unstable angina. Body?S4. differ from baseline. Body?S14. Apolipoprotein B percentage of differ from baseline. Body?S15. Funnel story: all\trigger mortality. Body?S16. Funnel story: cardiovascular mortality. Body?S17. Funnel story: myocardial infarction. Body?S18. Funnel story: stroke. Body?S19. Funnel story: coronary revascularization. Body?S20. Funnel story: unpredictable angina. Body?S21. Funnel story: congestive center failure exacerbation. Body?S22. Funnel story: neurocognitive undesirable events. Body?S23. Funnel story: diabetes mellitus. Body?S24. Funnel story: upsurge in creatine kinase. Body?S25. Funnel story: myalgia. Body?S26. Funnel story: upsurge in alanine or aspartate aminotransferase. Body?S27. Funnel story: treatment\emergent critical adverse events. Body?S28. Funnel story: low\thickness lipoprotein cholesterol. Body?S29. Funnel story: high\thickness lipoprotein cholesterol. Body?S30. Funnel story: total cholesterol. Body?S31. Funnel story: lipoprotein(a). Body?S32. Funnel story: apolipoprotein B. JAH3-6-e006910-s001.pdf (2.2M) GUID:?B76D4795-19CD-4743-BE4C-6B8263DB6790 Abstract Background We wanted to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab. Strategies and Outcomes We performed a organized review and meta\evaluation of randomized managed trials evaluating treatment with and without PCSK9 inhibitors; 35 randomized managed trials composed of 45?539 sufferers (mean follow\up: 85.5?weeks) were included. Mean age group was 61.02.8?years, and mean baseline low\thickness lipoprotein cholesterol was 10622?mg/dL. Weighed against no PCSK9 inhibitor therapy, treatment using a PCSK9 inhibitor was connected with a lower price of myocardial infarction (2.3% versus 3.6%; chances proportion [OR]: 0.72 [95% confidence interval (CI), 0.64C0.81]; worth of <0.05 was considered statistically significant. All analyses had been performed using Review Supervisor edition 5.3 (RevMan; Cochrane Cooperation) and In depth Meta\Analysis Software edition 3.3 (Biostat, Inc). Outcomes Research Selection and Individual People The PRISMA research id flowchart for today's evaluation is proven in Body?S1. A complete of 138 research hands from 35 research were analyzed, composed of 45?539 sufferers (Desk?S1).5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, AF6 38, 39, 40, 41, 42, 43 Alirocumab was found in 18 research (28 treatment hands), and evolocumab was found in 17 research (39 treatment hands; Body?1); placebo was the most frequent control utilized (52 control hands), with ezetimibe found in 17 hands, and regular therapy in 2 hands. Eight research were of the exclusively FH inhabitants, and 5 research included only individuals intolerant to statins. Mean treatment length in the randomized inhabitants up to enough time of confirming was 85.5?weeks (range: 8C113?weeks). Open up in another window Shape 1 Timeline of randomized managed tests of alirocumab and evolocumab. FDA shows US Meals and Medication Administration; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia. Baseline affected person characteristics for the analysis hands included are demonstrated in Desk?S2. Mean age group was 61.02.8?years, and 67.6% of individuals were men; the suggest baseline LDL\C was 106.022.3?mg/dL (2.70.6?mmol/L). Nearly all study individuals (91.8%) had been on steady statin therapy at baseline, and 58.4% were on a rigorous statin routine. From 45?539 total patients in the randomized population, safety data had been available and abstracted for 45?503 (99.9%). Threat of methodological bias was evaluated as lower o-Cresol in many research (Shape?S2). All\Trigger Mortality Thirty\five RCTs (45?503 individuals) were contained in the evaluation of most\trigger mortality (Shape?2). Weighed against no treatment having a PCSK9 inhibitor, treatment having a PCSK9 inhibitor had not been connected with a statistically significant modification in mortality (crude price, 1.9% versus 2.2%; OR: 0.71 [95% CI, 0.47C1.09]; P=0.12, We2=18%, heterogeneity P=0.26). Random results metaregression showed a substantial association between baseline LDL\C and all\trigger mortality advantage (P=0.038; Shape?3). Open up in another window Shape 2 All\trigger mortality. Forrest storyline showing the chances percentage for all\trigger mortality with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) weighed against no PCSK9i. The pooled chances ratio was determined with random results based on the Mantel\Haenszel (M\H) technique. Marker size can be proportional to the analysis weight. CI shows confidence interval. Open up in another window Shape 3 Research\level metaregression evaluation with random results showing the partnership between baseline low\denseness lipoprotein cholesterol (LDL\C) and all\trigger mortality. Group size can be proportional to the analysis weight; 95% self-confidence intervals demonstrated in blue. Cardiovascular Mortality Thirty\four RCTs (44?701 individuals) were contained in the evaluation of cardiovascular mortality (Shape?4). Weighed against no treatment having a PCSK9 inhibitor, treatment having a PCSK9 inhibitor had not been connected with a statistically significant modification in cardiovascular mortality (crude price, 1.1% versus 1.3%; OR: 1.01 [95% CI, 0.85C1.19]; P=0.95, I2=0%, heterogeneity P=0.74). Open up in another window Shape 4 Cardiovascular mortality. Forrest storyline showing the chances.Because this PCSK9 inhibitor shall not really become designed for clinical use, we elected never to include bococizumab tests in our research. Our meta\evaluation has a number of important restrictions. heart failing exacerbation. Shape?S5. Diabetes mellitus. Shape?S6. Upsurge in creatine kinase. Shape?S7. Myalgia. Shape?S8. Alanine or aspartate aminotransferase boost. Shape?S9. Treatment\emergent significant adverse events. Shape?S10. Low\denseness lipoprotein cholesterol percentage of differ from baseline. Shape?S11. Large\denseness lipoprotein cholesterol percentage of differ from baseline. Shape?S12. Total cholesterol percentage of differ from baseline. Shape?S13. Lipoprotein(a) percentage of differ from baseline. Shape?S14. Apolipoprotein B percentage of differ from baseline. Shape?S15. Funnel plot: all\cause mortality. Figure?S16. Funnel plot: cardiovascular mortality. Figure?S17. Funnel plot: myocardial infarction. Figure?S18. Funnel plot: stroke. Figure?S19. Funnel plot: coronary revascularization. Figure?S20. Funnel plot: unstable angina. Figure?S21. Funnel plot: congestive heart failure exacerbation. Figure?S22. Funnel plot: neurocognitive adverse events. Figure?S23. Funnel plot: diabetes mellitus. Figure?S24. Funnel plot: increase in creatine kinase. Figure?S25. Funnel plot: myalgia. Figure?S26. Funnel plot: increase in alanine or aspartate aminotransferase. Figure?S27. Funnel plot: treatment\emergent serious adverse events. Figure?S28. Funnel plot: low\density lipoprotein cholesterol. Figure?S29. Funnel plot: high\density lipoprotein cholesterol. Figure?S30. Funnel plot: total cholesterol. Figure?S31. Funnel plot: lipoprotein(a). Figure?S32. Funnel plot: apolipoprotein B. JAH3-6-e006910-s001.pdf (2.2M) GUID:?B76D4795-19CD-4743-BE4C-6B8263DB6790 Abstract Background We sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab. Methods and Results We performed a systematic review and meta\analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45?539 patients (mean follow\up: 85.5?weeks) were included. Mean age was 61.02.8?years, and mean baseline low\density lipoprotein cholesterol was 10622?mg/dL. Compared with no PCSK9 o-Cresol inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64C0.81]; value of <0.05 was considered statistically significant. All analyses were performed using Review Manager version 5.3 (RevMan; Cochrane Collaboration) and Comprehensive Meta\Analysis Software version 3.3 (Biostat, Inc). Results Study Selection and Patient Population The PRISMA study identification flowchart for the present analysis is shown in Figure?S1. A total of 138 study arms from 35 studies were analyzed, comprising 45?539 patients (Table?S1).5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Alirocumab was used in 18 studies (28 treatment arms), and evolocumab was used in 17 studies (39 treatment arms; Figure?1); placebo was the most common control used (52 control arms), with ezetimibe used in 17 arms, and standard therapy in 2 arms. Eight studies were of an exclusively FH population, and 5 studies included only patients intolerant to statins. Mean treatment duration in the randomized population up to the time of reporting was 85.5?weeks (range: 8C113?weeks). Open in a separate window Figure 1 Timeline of randomized controlled trials of alirocumab and evolocumab. FDA indicates US Food and Drug Administration; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia. Baseline patient characteristics for the study arms included are shown in Table?S2. Mean age was 61.02.8?years, and 67.6% of participants were men; the mean baseline LDL\C was 106.022.3?mg/dL (2.70.6?mmol/L). The majority of study participants (91.8%) were on stable statin therapy at baseline, and 58.4% were on an intensive statin routine. From 45?539 total patients in the randomized population, safety data were available and abstracted for 45?503 (99.9%). Risk of methodological bias was assessed as low in most studies (Number?S2). All\Cause Mortality Thirty\five RCTs (45?503 participants) were included in the analysis of most\cause mortality (Number?2). Compared with no treatment having a PCSK9 inhibitor, treatment having a PCSK9 inhibitor was not associated with a statistically significant switch in mortality (crude rate, 1.9% versus 2.2%; OR: 0.71 [95% CI, 0.47C1.09]; P=0.12, I2=18%, heterogeneity P=0.26). Random effects metaregression showed a significant association between baseline LDL\C and all\cause mortality benefit (P=0.038; Number?3). Open in a separate window Number 2 All\cause mortality. Forrest storyline showing the odds percentage for all\cause mortality with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was determined with random effects according to the Mantel\Haenszel (M\H) method. Marker size is definitely proportional to the study weight. CI shows confidence interval. Open in a separate window Number 3 Study\level metaregression analysis with random effects showing the relationship between baseline low\denseness lipoprotein cholesterol (LDL\C) and all\cause mortality. Circle size is definitely proportional to the study weight; 95% confidence intervals demonstrated in blue. Cardiovascular Mortality Thirty\four RCTs (44?701 participants) were included in the analysis of cardiovascular mortality (Number?4). Compared with no treatment having a PCSK9 inhibitor, treatment having a PCSK9 inhibitor was not associated with a statistically significant switch in.Random effects metaregression showed a significant association between baseline LDL\C and all\cause mortality benefit (P=0.038; Number?3). Open in a separate window Figure 2 All\cause mortality. storyline: stroke. Number?S19. Funnel storyline: coronary revascularization. Number?S20. Funnel storyline: unstable angina. Number?S21. Funnel storyline: congestive heart failure exacerbation. Number?S22. Funnel storyline: neurocognitive adverse events. Number?S23. Funnel storyline: diabetes mellitus. Number?S24. Funnel storyline: increase in creatine kinase. Number?S25. Funnel storyline: myalgia. Number?S26. Funnel storyline: increase in alanine or aspartate aminotransferase. Number?S27. Funnel storyline: treatment\emergent severe adverse events. Number?S28. Funnel storyline: low\denseness lipoprotein cholesterol. Number?S29. Funnel storyline: high\denseness lipoprotein cholesterol. Number?S30. Funnel storyline: total cholesterol. Number?S31. Funnel storyline: lipoprotein(a). Number?S32. Funnel storyline: apolipoprotein B. JAH3-6-e006910-s001.pdf (2.2M) GUID:?B76D4795-19CD-4743-BE4C-6B8263DB6790 Abstract Background We sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab. Methods and Results We performed a systematic review and meta\analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45?539 individuals (mean follow\up: 85.5?weeks) were included. Mean age was 61.02.8?years, and mean baseline low\denseness lipoprotein cholesterol was 10622?mg/dL. Compared with no PCSK9 inhibitor therapy, treatment having a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds percentage [OR]: 0.72 [95% confidence interval (CI), 0.64C0.81]; value of <0.05 was considered statistically significant. All analyses were performed using Review Manager version 5.3 (RevMan; Cochrane Collaboration) and Comprehensive Meta\Analysis Software version 3.3 (Biostat, Inc). Results Study Selection and Patient Populace The PRISMA study recognition flowchart for the present analysis is demonstrated in Physique?S1. A total of 138 study arms from 35 studies were analyzed, comprising 45?539 patients (Table?S1).5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Alirocumab was used in 18 studies (28 treatment arms), and evolocumab was used in 17 studies (39 treatment arms; Physique?1); placebo was the most common control used (52 control arms), with ezetimibe used in 17 arms, and standard therapy in 2 arms. Eight studies were of an exclusively FH population, and 5 studies included only patients intolerant to statins. Mean treatment duration in the randomized population up to the time of reporting was 85.5?weeks (range: 8C113?weeks). Open in a separate window Physique 1 Timeline of randomized controlled trials of alirocumab and evolocumab. FDA indicates US Food and Drug Administration; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia. Baseline patient characteristics for the study arms included are shown in Table?S2. Mean age was 61.02.8?years, and 67.6% of participants were men; the mean baseline LDL\C was 106.022.3?mg/dL (2.70.6?mmol/L). The majority of study participants (91.8%) were on stable statin therapy at baseline, and 58.4% were on an intensive statin regimen. From 45?539 total patients in the randomized population, safety data were available and abstracted for 45?503 (99.9%). Risk of methodological bias was assessed as low in most studies (Physique?S2). All\Cause Mortality Thirty\five RCTs (45?503 participants) were included in the analysis of all\cause mortality (Physique?2). Compared with no treatment with a PCSK9 inhibitor, treatment with a PCSK9 inhibitor was not associated with a statistically significant change in mortality (crude rate, 1.9% versus 2.2%; OR: 0.71 [95% CI, 0.47C1.09]; P=0.12, I2=18%, heterogeneity P=0.26). Random effects metaregression showed a significant association between baseline LDL\C and all\cause mortality benefit (P=0.038; Physique?3). Open in a separate window Physique 2 All\cause mortality. Forrest plot showing the odds ratio for all\cause mortality with PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors (PCSK9i) compared with no PCSK9i. The pooled odds ratio was calculated with random effects according to the Mantel\Haenszel (M\H) method. Marker size is usually proportional to the study weight. CI indicates confidence interval. Open in a separate window Physique 3 Study\level metaregression analysis with random effects showing the relationship between baseline low\density lipoprotein cholesterol (LDL\C) and all\cause mortality. Circle size is usually proportional to the study weight; 95% confidence intervals shown in blue. Cardiovascular Mortality Thirty\four RCTs (44?701 participants) were included in the analysis of cardiovascular mortality (Physique?4). Compared with no treatment with a PCSK9 inhibitor,.