The DIG trials
The DIG trial was actually two trials, although the second one (DIG-PEF) has been largely forgotten. In what has been called the main trial (that restricted to HF-REF patients) 6,800 HF patients with LVEF of 45 % or less were randomly assigned to digoxin or placebo. The primary outcome of all-cause mortality was unchanged and of the secondary outcomes HF hospitalisation prevention showed a marked effect (26.8 % versus 34.7 %, risk ratio 0.72 [0.66 to 0.79]; p<0.001). The combined endpoint of 
death from any cause or hospitalisation for worsening HF was significantly lower in the digoxin group (risk ratio, 0.85; 95 % confidence interval [CI] 0.79 to 0.91; p<0.001). The HF-PEF study was smaller (988 patients with LVEF >45 %) and chose the combined endpoint of death or hospitalisation due to worsening HF as the primary outcome. The result of DIG-PEF as they quaintly put it the trial publication was “With regard to the combined outcome of death or hospitalisation due to worsening HF, the results in the ancillary trial (risk ratio, 0.82; 95 percent confidence interval, 0.63 to 1.07) were consistent with the findings of the main trial.” Thus although being manifestly underpowered, the DIG-PEF trial just missed its primary endpoint statistically. Had the combined DIG trial used this combined endpoint it would have been easily positive for the clinically acceptable combined endpoint of death or HF hospitalisation and the results in HF-REF and HF-PEF would have been indistinguishable.
SENIORS
The SENIORS15,16 trial recruited both types if HF was powered with a single primary endpoint of death or CV hospitalisation. SENIORS in 2,128 HF patients aged ≥70 years showed a 14 % reduction in the primary outcome of all-cause mortality or CV hospital admission (hazard ratio [HR] 0.86, 95 % CI 0.74–0.99; p=0.039). It was a positive trial and LVEF had no impact of the treatment effect with the point estimate of benefit in those patients with a LVEF >35 % being slightly bigger than those with LVEF ≤35 % (see Figure 3). For SENIORS the overall trial was positive and the subset with preserved LVEF did just as well, there was no statistically significant interaction between LVEF and treatment effect yet guidelines fail to recommend nebivolol other than for lower EF. This is even though this is based on an analysis of a subset of the pre-specified question and the authors maintain that because the HF-PEF subset was not independently significant nebivolol cannot be recommended for this cohort. This is despite the fact that the correct statistical analysis is to assume any subset behaves as the whole cohort unless there is a reason or a statistical suggestion that it does not. Nebivolol should therefore be recommended for elderly HF patients irrespective of LVEF. None of the guidelines follow this logic, and in doing so are themselves illogical.
The Trials that did Recruit Heart Failure with Preserved Ejection Fraction Patients
There have been four M+M trials that have specifically and solely recruited HF-PEF patients: CHARM-Preserved,17 PEP-CHF,18 I-Preserve19 and TOPCAT.20
CHARM-Preserved
The CHARM programme actually represents a type of hybrid of the two types of trial mentioned above. The CHARM programme of candesartan is made up of three component trials that were in addition combined together prospectively with a single powered endpoint and recruited and analysed together. It thus could be thought of as a single trial (the programme) with a HF-PEF subset (CHARM-preserved)21 or three trials, one of which CHARM-preserved is in HF-PEF. If analysed the first way the overall programme was negative as the primary endpoint was not reached. Seven thousand five hundred and ninety-nine CHF patients were randomised to candesartan 32 mg or placebo and the primary endpoint of all-cause mortality was not statistically significantly reduced: 23 versus 25 %, HR 0.91, 95 % CI 0.83–1.00; p=0.055. We should therefore not even look at the HF-PEF or HF-REF cohorts for efficacy in these subsets. The CHARM-Preserved trial alone was powered for the composite of CV death or HF hospitalisation. In 3,023 patients, candesartan did not significantly reduce the primary endpoint (unadjusted HR 0.89 [95 % CI 0.77–1.03]; p=0.118), but it came very close (covariate adjusted HR 0.86 [0.74–1.0]; p=0.051).
PEP-CHF
PEP-CHF was a randomised, double-blind trial, comparing placebo with perindopril, 4 mg/day in patients aged >70 years with a diagnosis of HF, and echocardiographic evidence of diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease. The primary endpoint was a composite of all-cause mortality and unplanned HF-related hospitalisation: 850 patients were randomised and followed-up for an average of 2.1 years. The power of the study to show a difference in the primary endpoint was reported to be only 35 % (because of poor recruitment and lower than expected event rates) showing only a one-third chance of showing an effect event if a real effect were present. Overall, 107 patients assigned to placebo and 100 assigned to perindopril reached the primary endpoint (HR 0.919, 95 % CI 0.700–1.208; P=0.545). By 1 year, before the extent of loss of adherence to randomised drug groups had become so catastrophically high as mentioned earlier, the reductions in the primary outcome (HR 0.692, 95 % CI 0.474–1.010; p=0.055) and hospitalisation for HF (HR 0.628, 95 % CI 0.408–0.966; p=0.033) were observed and functional class (p=0.030) and 6-minute corridor walk distance (p=0.011) had improved in those assigned to perindopril.
I-PRESERVE
I-Preserve similarly was a randomised double-blind placebo-controlled trial in HF-PEF, but in this case was much larger. Four thousand one hundred and twenty-eight patients 60 years or older and LVEF >45 % were randomised for an average of 49.5 months to 300 mg of irbesartan or placebo. The primary endpoint was death or CV hospitalisation. The primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group, giving primary event rates of 100.4 and 105.4 per 1,000 patient-years, respectively (HR 0.95, 95 % CI 0.86 to 1.05; p=0.35). The mortality rates were similar. This result seems disappointing but it is directionally and in scale not dissimilar to the result of VAL-Heft22 of valsartan in HF-REF where in 5,010 patients 160 mg of valsartan reduced the primary mortality/ morbidity endpoint, by 13.2 % (relative risk 0.87, 97.5 % CI 0.77 to 0.97; p=0.009), with no difference in mortality. Also in I-PRESERVE there was a high rate of discontinuation of study treatment (34 % by the end of the study) and a high rate of concomitant use of ACE inhibitors, spironolactone and beta-blockers.