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Table 1 Summary of included studies, including the disease area, original trial question, category of causal question, methods used and result of causal analysis

From: Application of causal inference methods in the analyses of randomised controlled trials: a systematic review

Study

Disease area

Trial question

Causal category

Causal question

Causal method

Causal result summary

Alexander (2014) [22]

Cardiovascular disease

Comparative effectiveness of apixaban vs warfarin in patients with atrial fibrillation for risk of cardiovascular and thromboembolic endpoints

Concomitant medication

What is the effect of aspirin use on risk of cardiovascular and thromboembolic endpoints?

MSM with IPW [9]

Evidence of an increased risk of stroke or major bleeding from aspirin use as a concomitant medication on top of apixiban or warfarin

Bobo (2014) [26]

Mental health

Comparative effectiveness of lithium vs quetiapine on clinical outcomes in patients with bipolar disorder

Concomitant medication

What is the effect of benzodiazepine use on core bipolar mood symptoms?

MSM with IPW [3]

No statistically significant effect of benzodiazepine use on any of the outcomes, though there were extremely wide confidence intervals both before and after IPW

Cook (2013) [43]

Transfusion medicine

Non inferiority of pathogen inactivated platelets vs standard platelets for successful blood transfusion (MIRASOL study)

Dosing/duration

What is the probability of overall success in increasing platelet count over 28 days while correctly taking into account number of transfusions needed?

MSM with IPW [3, 6, 9]

A reduced probability of transfusion success with increasing transfusion number was observed in the weighted analyses, but the effect was smaller than was observed in the original trial analysis

Crook (2014) [17]

HIV

Safety and efficacy of a microbicide gel vs placebo to prevent HIV transmission in women with HIV positive partners in Sub Saharan Africa (MDP301 trial)

Concomitant medication

What is the causal effect of hormonal contraception (injectable and oral) on HIV incidence?

MSM with IPW [3, 14]

Evidence of an elevated risk of HIV infection with use of DMPA but no other hormonal contraceptives.

Kataoka (2012) [23]

Diabetes

Efficacy of voglibose, nateglinide and lifestyle interventions on changes in coronary atherosclerosis in patients with early-stage diabetes mellitus

Concomitant medication

What is the effect of treatment with statins, ACE inhibitors and ARBs (considered separately as three classes of concomitant medications) on atheroma progression as measured by total lesion length (TLL)?

MSM with IPW [3, 9]

Use of statins was estimated to increase TLL. No evidence of an effect of any other concomitant medications examined

Li (2012) [36]

HIV

Placebo-controlled comparison of three ART regimens: ABC/3TC/ZDV, 3TC/ZDV + EFV, ABC/3TC/ZDV + EFV

Treatment timing

What is the effect of switching early (within 8 weeks) vs late (after 8 weeks) onto a second-line therapy after first virologic failure on CD4 count and other clinical markers of HIV severity?

IPW [37]

Switching early results in better clinical outcomes for all three clinical measures examined than switching late

Lipkovich (2008) [41]

Mental health

Trial 1. Efficacy and safety of olanzapine vs haloperidol in terms of clinical scores and quality of life in acute bipolar patients Trial 2. Efficacy and safety of olanzapine vs risperidone in terms of clinical scores in schizophrenic patients

Dosing/duration

What is the effect of dosage of olanzapine on change in disease severity measures? Estimated separately in each trial

MSM with IPW [3, 9, 49]

No strong evidence of differences in response with changing dose of olanzapine, though in one study the weighted analysis was suggestive of a negative dose effect at weeks 20 and 24 only.

London (2010) [34]

Cancer

Superiority of TOPO vs TOPO with CTX (chemotherapy combinations) for response to treatment in recurrent or refractory neuroblastoma in children.

Sequential treatments

What is the best chemotherapy combination for first line treatment after adjusting for the optimal off-protocol treatment for survival at 2 years?

G estimation of an optimal Structural Nested Model [29, 35]

Under the assumption that all patients received the optimal off-protocol therapy, there were no detectable differences between TOPO and TOPO with CTX (2-year survival 40% vs 33%, p = 0.215)

McCoy (2013) [19]

HIV

Safety and efficacy of diaphragm, lubricant gel and condoms vs condoms alone to prevent HIV transmission in women in Sub Saharan Africa (MIRA study)

Concomitant medication

What is the effect of hormonal contraception (injectable and oral) on HIV incidence?

MSM with IPW [51]

No strong evidence of effect of oral contraceptives on HIV transmission, small suggestion of increased risk for injectable contraception

Morrison (2012) [18]

HIV

Safety and efficacy of a microbicide gel vs placebo to prevent HIV transmission in women in South Africa (Carraguard study)

Concomitant medication

What is the effect of hormonal contraception (injectable and oral) on HIV incidence?

MSM with IPW [3, 6]

No strong evidence of effect of oral or injectable contraceptives on HIV transmission, but possibility of an increased risk with use of DMPA

Rosenblum (2009) [20]

HIV

Safety and efficacy of diaphragm, lubricant gel and condoms vs condoms alone to prevent HIV transmission in women in Sub Saharan Africa (MIRA study)

Concomitant medication

What is the effect of the intervention controlling for condom use as a mediator, and what is the direct effect of condom use on HIV transmission?

MSM with IPW [6]

No evidence of a difference in HIV risk between treatment arms after controlling for overall condom use. Condom use was estimated to be protective in both trial arms, though was only statistically significant in one arm

Rosthøj (2011) [39]

Cancer

Effect of blood counts only (control) vs blood counts and pharmacokinetic parameters to make therapy decisions on relapse in acute lymphoblastic leukaemia in children.

Dosing/duration

How should dose of oral therapy be adjusted (increase, no change, decrease, pause) in response to a given white blood cell count to obtain a future white blood cell count within the target range within a given time frame (e.g. within two weeks). How do the estimated optimal strategies compare to the original protocol?

History Adjusted MSM using IPW [40]

Optimal strategy estimated by the model was broadly consistent with the actual protocol for treatment dosing; however, where protocol suggested moderate reduction in dose, the MSM more often suggested no change, and where a moderate increase in dose was suggested by protocol, the MSM more frequently suggested a large increase to be the optimal choice.

Severus (2010) [42]

Mental health

Efficacy of olanzapine vs lithium in prevention of mood episode relapse or recurrence in patients with bipolar disorder

Dosing/duration

What is the effect of dosage of lithium and olanzapine on recurrence of symptoms?

MSM with IPW for probability of high/low dose at each interval [3]

High and medium lithium doses were shown to reduce risk of manic/mixed episode compared to low doses, but here was no evidence of an effect on risk of depressive episodes as confidence intervals were wider (although estimates were similar) Higher doses of olanzapine were associated with lower risk of depressive episodes but not manic/mixed episodes

Shen (2013) [24] (similar analysis also presented in [52])

Diabetes

Efficacy of two drugs (nateglinine or valsartan) on conversion to diabetes and CV outcomes in patients with impaired glucose tolerance and other CV risk factors.

Concomitant medication

What is the effect of use of beta blockers, diuretics, and statins on onset of Type 2 diabetes?

MSM with IPW [3]

Use of statins and diuretics found to increase risk of diabetes onset

Shinozaki (2012) [27]

Diabetes

Effect of intensive (target HbA1c 6.9 or less, BMI < 25, BP < 130/80) vs conventional treatment (no target levels) strategies for type 2 diabetes in elderly patients on risk of morality, cardiovascular events and other diabetes related endpoints

Concomitant medication

Is there a preventative effect of atorvastatin on cardiovascular disease and on diabetic vascular complications?

MSM with IPW, structural nested failure time models with g-estimation [3, 53]

Atorvastatin estimated to be protective against both cardiovascular events and diabetes related events, though confidence intervals for cardiovascular events were very wide.

Shortreed (2012) [38]

Mental health

Efficacy and tolerability of antipsychotic medications (perphenazine vs olanzapine/risperidone/quetiapine/ziprasidone) in patients with schizophrenia on time to failure of treatment (time to first switch)

Treatment timing

What is the optimal therapeutic strategy in terms of initial threshold of PANSS score (a scale of psychotic symptoms) to switch to an atypical antipsychotic drug over perphenazine to minimise schizophrenic symptoms and maximise quality of life over 12 months?

Dynamic MSM with IPW [54]

No differences detected between the different dynamic regimes for 12-onth quality of life. All strategies predicted improvements in PANSS by 12 months. There was no significant difference between 12 months PANSS score between the strategies of “always treat with perphenazine” and “always treat with atypical antipsychotic”, but it was observed that if starting with perphenazine, PANSS at 12 months was increased if the threshold to switch was higher (i.e. when the patient was more likely to switch).

VandeboscH (2005) [44]

HIV

Safety and efficacy of a microbicide gel vs placebo to prevent HIV transmission in women in Africa

Dosing/duration

What is the effect of cumulative gel use on development of vaginal lesions prior to HIV diagnosis?

Structural accelerated failure time model [55]

Increased experimental gel use was found to reduce time to first or any lesion compared to placebo gel, suggesting it may increase risk of lesions compared to placebo gels.

Wahed (2013) [31]

Cancer

Effect of adding all trans retinoic acid (ATRA), granulocyte colony stimulating factor (GCSF) or both to fludarabine plus cytosine arabinoside plus idarubicin (FAI) as a first-line (induction) therapy on the probability of success (alive and in complete remission at 6 months) in treatment of acute leukaemia

Sequential treatments

What is the best combined induction (randomised) and salvage (non-randomised) strategy to improve overall survival?

G formula MSM with IPW [1, 3, 56]

Both methods gave results consistent with FAI plus ATRA being the best remission induction therapy. If patient’s disease was resistant to that therapy, then salvage therapy options were equivocal. If a patient relapsed after CR with FAI plus ATRA then salvage therapy with HDAC was superior

Walker (2010) [21]

HIV

Effect of laboratory monitoring in addition to clinical monitoring of patients with HIV in Africa on clinical endpoints and mortality.

Concomitant medication

What is the effect of use of cotrimoxazole on survival, WHO stage 3 and 4 events, malaria and CD4 counts in adults after ART initiation?

MSM with IPW [3]

Use of cotrimoxazole was estimated to improve survival and reduce malaria infection in adults on ART Reduction in mortality was greatest in first 18 months of ART

Wang (2012) [28]

Cancer

A sequential multiple assignment randomised trial (SMART) designed to evaluate and compare 12 different sequential rules for switching from initial combination chemotherapy to second chemotherapy in prostate cancer, in terms of overall response to treatment and overall survival.

Sequential treatments

What is the best overall strategy to maximise response to treatment (“success”) after re-defining the possible treatment regimens to be viable treatment regimens allowing switches to non-randomised therapy.

Dynamic MSM with IPW [30, 37]

Different combinations were estimated to be optimal based on different measures of “success” Wide confidence intervals and large number of comparisons meant statistical comparison between actual scores was not feasible

Zhang (2012) [25]

Cardiovascular disease

Effect of felodipine in addition to hydrochlorothiazide after 6 weeks of therapy (i.e. intensive blood pressure reduction vs standard care) in a population of Chinese patients at risk of cardiovascular disease, on reduction in various cardiovascular endpoints (e.g. stroke)

Concomitant medication

What is the effect of add-on therapy (in the form of an increased dose of hydrochlorothiazide and/or other antihypertensive agents excluding calcium antagonists) in addition to randomised therapy on trial outcomes?

MSM with IPW [9]

Absence of add-on therapy was found to be protective for stroke, all-cause mortality and all cardiovascular events, despite the add on therapy reducing systolic and diastolic blood pressure

Zhang (2013) [33] (similar analysis also presented in [57])

Cancer

Effect of petrexemed in addition to cisplatin in patients with malignant pleural mesothelioma in terms of time to response and overall survival

Sequential treatments

What is the effect of the randomised first-line treatment if secondary treatments and discontinuation of study treatment are correctly adjusted for?

MSM with IPW [6]

Addition of petrexemed found to be beneficial in comparison to cisplatin only, with a smaller HR estimated via causal methods compared to ITT analysis

Yamaguchi (2004) [32]

Cancer

Superiority of CPT-P vs VDS-P and non-inferiority of CPT vs VDS-P (chemotherapy combinations) for survival in non-small cell lung cancer

Sequential treatments

What is the direct effect of the randomised treatment for the (CPT-P vs VDS-P) on survival, accounting for imbalances in second-line therapy?

MSM with IPW, G –estimation of structural nested models [3, 49, 58]

CPT-P was not shown to be beneficial compared to VDS-P and no difference was observed between the two different second line therapies in terms of survival

Platt (2012) [45]

Paediatrics

Effect of breast feeding intervention on prevalence and length of exclusive breastfeeding, and weight, height, and infection rates by 12 months

Dosing/duration

What is the effect of length of breast feeding on weight (kg) at 12 months?

MSM with IPW [3]

Fitted mean 12-month weight (kg) highest for 2 months exclusive breastfeeding and lowest for 9–12 months exclusive breastfeeding

Moodie (2009) [46]

Paediatrics

Effect of breast feeding intervention on various 12-month endpoints such as prevalence and length of exclusive breastfeeding; and weight, height, and infection rates in children

Dosing/duration

What is the effect of length of breast feeding on weight (kg) and length (cm) at 12 months?

G-estimation of structural nested models [29, 35, 59]

Breastfeeding to at least 9 months optimised 12-month weight and length

  1. MSM marginal structural model, IPW inverse probability (of treatment) weighting, DMPA depo-medroxyprogesterone acetate, ART antiretroviral therapy, TOPO topotecan, CTX cyclophosphamide, ABC abacavir, 3TC lamivudine, ZDV zidovudine, EFV efavirenz, CPT-P irinotecan plus cisplatin, VDS-P vindesine plus cisplatin, CPT irinotecan, ACE angiotensin-converting enzyme, ARBs angiotensin II receptor blockers, PANSS positive and negative syndrome scale, WHO World Health Organisation, HR hazard ratio, ITT intention to treat