Abstract: One hundred and twelve studies met our selection criteria: 15 were studies of adults with CKD; 16 studies were conducted in the general population but provided subgroup data for people with CKD; and 81 studies included individuals with CKD, however, data for this subgroup were not provided. The risk of bias in all 112 studies was frequently high or unclear. Of the 31 studies (23,762 participants) with data on CKD patients, follow-up ranged from three months to five years, and study size ranged from 16 to 2916 participants. In total, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta-analyses. In acute heart failure, the effects of adenosine A1-receptor antagonists, dopamine, nesiritide, or serelaxin on death, hospitalisations, worsening heart failure or kidney function, hyperkalaemia, hypotension or quality of life were uncertain due to sparse data or were not reported. In chronic heart failure, the effects of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) (4 studies, 5003 participants: RR 0.85, 95% CI 0.70 to 1.02; I2 = 78%; low certainty evidence), aldosterone antagonists (2 studies, 34 participants: RR 0.61 95% CI 0.06 to 6.59; very low certainty evidence), and vasopressin receptor antagonists (RR 1.26, 95% CI 0.55 to 2.89; 2 studies, 1840 participants; low certainty evidence) on death (any cause) were uncertain. Treatment with beta-blockers may reduce the risk of death (any cause) (4 studies, 3136 participants: RR 0.69, 95% CI 0.60 to 0.79; I2 = 0%; moderate certainty evidence). Treatment with ACEi or ARB (2 studies, 1368 participants: RR 0.90, 95% CI 0.43 to 1.90; I2 = 97%; very low certainty evidence) had uncertain effects on hospitalisation for heart failure, as treatment estimates were consistent with either benefit or harm. Treatment with beta-blockers may decrease hospitalisation for heart failure (3 studies, 2287 participants: RR 0.67, 95% CI 0.43 to 1.05; I2 = 87%; low certainty evidence). Aldosterone antagonists may increase the risk of hyperkalaemia compared to placebo or no treatment (3 studies, 826 participants: RR 2.91, 95% CI 2.03 to 4.17; I2 = 0%; low certainty evidence). Renin inhibitors had uncertain risks of hyperkalaemia (2 studies, 142 participants: RR 0.86, 95% CI 0.49 to 1.49; I2 = 0%; very low certainty). We were unable to estimate whether treatment with sinus node inhibitors affects the risk of hyperkalaemia, as there were few studies and meta-analysis was not possible. Hyperkalaemia was not reported for the CKD subgroup in studies investigating other therapies. The effects of ACEi or ARB, or aldosterone antagonists on worsening heart failure or kidney function, hypotension, or quality of life were uncertain due to sparse data or were not reported. Effects of anti-arrhythmic agents, digoxin, phosphodiesterase inhibitors, renin inhibitors, sinus node inhibitors, vasodilators, and vasopressin receptor antagonists were very uncertain due to the paucity of studies. The effects of pharmacological interventions for heart failure in people with CKD are uncertain and there is insufficient evidence to inform clinical practice. Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.

Plain-language summary: We found 31 studies involving 23,762 people with heart failure and chronic kidney disease. Patients were given either a heart failure medicine compared to standard care or a placebo. The treatment they received was decided by random chance. Although there were many different treatments studied, unfortunately, few of them looked at the same type of medicine. As well, there were many different ways that researchers measured what happened when patients took these medicines. As a result, we could not combine the studies together and clarify the benefits and harms of each treatment. Existing studies cannot really tell us whether medicines used to treat heart failure in the general population are effective or safe for people who have both heart failure and chronic kidney disease. We are not able to recommend which heart failure medicines are best for people with heart failure and chronic kidney disease. We need more information from large clinical studies. Most of the heart failure studies did not report treatment effects separately based on levels of kidney function. Obtaining this information from existing studies may be helpful to learn more about how to treat heart failure in people with chronic kidney disease.