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Gender, Cancer, Diabetes Among Predictors of Mortality for Patients With HFpEF


Event-free survival rates were higher in women compared with men for all-cause mortality and first heart failure hospitalization.

Being male or having cancer, diabetes, or higher tricuspid regurgitation peak velocity (TRV), a key heart valve measure, are predictors of long-term mortality and hospitalization for patients with heart failure with preserved ejection fraction (HFpEF), according to a study published in ESC Heart Failure.

HFpEF, also called diastolic heart failure, occurs when the left ventricle does not properly fill with blood when the heart is pumping; thus, the amount of blood that pumps out through the body is insufficient. This type of heart failure is more difficult to treat than heart failure with reduced ejection fraction.

The Karolinska-Rennes (KaRen) study was a multicenter study with a goal of characterizing and identifying prognostic factors for morbidity and mortality in HFpEF. Study criteria included patients with left ventricle ejection fraction (LVEF) of at least 45%, although guidelines in the United States establish HFpEF once LVEF reaches 50%.

The authors noted that studies of mortality rates in HFpEF have been inconsistent; rates have been lower in clinical trials compared with real-world studies. “Mortality rates in HFpEF are comparable with HFrEF, although survival seems to increase over time in HFrEF but not in HFpEF, which could be a result of emerging effective treatment in HFrEF but not HFpEF,” they wrote.

However, HFpEF has seen some therapeutic advances in the past year, with the first FDA approved treatment for the condition earlier this year (Entresto), and more results anticipated later this month at the European Society of Cardiology virtual meeting.

The study’s primary outcome found that 1-, 3-, 5-, and 10-year rates of mortality or first heart failure (HF) hospitalization were 35%, 54%, 67%, and 84%, respectively. The secondary outcome found that 1-, 3-, 5-, and 10-year all-cause death rates were 15%, 31%, 47%, and 74%.

Between May 21, 2007, and December 29, 2011, 539 patients were enrolled in 3 centers in Sweden and 11 centers in France. Of this group, 438 patients returned in a stable state after 4–8 weeks for a follow-up visit, which included a detailed echocardiographic assessment, electrocardiogram, and clinical evaluation.

At enrollment, the median (IQR) age of the patients was 78 (72-84) years and 52% were female. Most had hypertension (78%) and atrial fibrillation (AF) or flutter (63%), 36% were obese, definedas a body mass index (BMI) ≥ 30 kg/m2), 26% had diabetes, and 45% had anemia. Out of 291 patients with a heart rate of at least 70 BPM, 67% had AF. Median follow-up was 5.44 years (2.0-7.89).

Patient characteristics independently associated with all-cause mortality or first HF hospitalization (primary outcome) were:

  • Female sex (hazard ratio [HR], 0.64; 95% CI, 0.41-0.98; P = .040)
  • Diabetes (HR, 1.75; 95% CI, 1.11-2.74; P = .016)
  • Cancer (HR, 1.75; 95% CI, 1.01-3.03; P = .045)
  • TRV (HR, 1.87; 95% CI, 1.34-2.62; P < .001)

Patient characteristics independently associated with higher risk of all-cause death (secondary outcome) were:

  • Higher age (HR, 1.03 per year; 95% CI, 1.00-1.06; P = .032)
  • Heart rate of at least 70 BPM (HR, 1.68; 95% CI, 1.04-2.71; P = .035)
  • Anemia (HR, 1.63; 95% CI, 1.05-2.53; P = .029)
  • Hyponatremia (HR, 2.69; 95% CI, 1.58-4.59; P < .001)
  • Elevated TRV (HR, 2.14; 95% CI, 1.48-3.08; P < .001

The study did not find an association between AF and primary or secondary outcomes.

Echocardiographic abnormalities such as TRV, left ventricular ejection fraction (LVEF), and systolic peak of mitral annulus velocity are crucial for phenotyping HFpEF and narrowing selection criteria for future clinical intervention trials. These factors, in addition to age and female sex, can assist in early prevention and treatment of comorbidities.

The study follow-up also found that event-free survival rates were higher in women compared with men for both the primary and secondary outcome.

Primary outcome, women vs men:

  • 1 year: 67% vs 63%
  • 3 years: 50% vs 42%
  • 5 years: 39% vs 26%
  • 10 years: 18% vs 12%

Secondary outcome, women vs men:

  • 1 year: 85% vs 83%
  • 3 years: 74% vs 64%
  • 5 years: 61% vs 44%
  • 10 years: 30% vs 21%

“Our study adds and extends the current understanding of sex differences in HFpEF, demonstrating that women with HF have higher survival rates compared with men over a long study period across a wide range of LVEFs, even after adjusting for clinical characteristics,” the authors concluded.


Shahim A, Hourqueig M, Donal E, et al. Predictors of long-term outcome in heart failure with preserved ejection fraction: a follow-up from the KaRen study. ESC Heart Fail. Published online August 10, 2021. doi:10.1002/ehf2.13533

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