Fixed-dose combination therapy for CVD prevention

Column-Dr Ramon Abarquez photoMedicine is Not an Exact Science

Ramon F. Abarquez, Jr., MD, EFACC, FAsCC, FPCP, FPCC, CSPSH

THE majority of cardiovascular clinical practice guidelines are based on expert opinion. Yet, there is high-quality evidence supporting the use of fixed-dose combination (FDC) therapy for cardiovascular disease (CVD) prevention. As in blood pressure guidelines recommended FDC therapy should be added to secondary prevention to increase adherence, at the lowest cost and with the greatest potential for scalability.

However, clinicians may be reluctant to offer FDCs outside of clinical norms, based on clinical practice guidelines’ recommendations. Fixed-dose combination remains a promising pragmatic strategy to improve adherence. Outcomes should continue to be researched so that its implementation will maximize benefit and minimize harm. (Huffman, PLoS Med. 2015 Aug 11;12(8):e1001862)


CVD is the leading cause of death and disability worldwide, yet CVD risk factor control and secondary prevention rates remain low. An FDC of blood pressure, cholesterol lowering and anti-platelet treatments into a single pill, or polypill, has been proposed for better adherence and lower costs.

Seven of the nine trials evaluated (six weeks to 15 months) FDC treatment on mortality is 1.2 percent versus control 1.0 percent (RR 1.26, CI 0.67 to 2.38, N = 3465) and on cardiovascular events, 4.0 percent versus control 2.9 percent, (RR 1.38, CI 0.91 to 2.10, N = 2479). Adverse events were common in both the intervention (30 percent) and comparator (24 percent) groups.

Participants randomized to FDC therapy being 20 percent (9-30 percent) have higher rate of discontinuation (14 percent versus 11 for control, RR 1.26, CI 1.02 to 1.55). The weighted mean differences in systolic and diastolic blood pressure between the intervention and control arms were -7.05 mmHg (-10.18 to -3.87) and -3.65 mmHg (-5.44 to -1.85), respectively. The weighted mean differences (95 percent CI) in total and LDL cholesterol between the intervention and control arms were -0.75 mmol/L (-1.05 to -0.46) and -0.81 mmol/L (-1.09 to -0.53), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (= 70 percent for all).

FDC therapy improved adherence to a multi-drug strategy by 33 percent (26 percent to 41 percent) compared with usual care, but this comparison was reported in only one study. The effects of FDC therapy on quality of life are uncertain, though these results were reported in only one trial. No trials reported costs. Reductions in blood pressure and lipid parameters are generally lower than those previously projected, though associated with modest increases in adverse events and with improved adherence to a multidrug regimen. (de Cates, Cochrane Database Syst Rev. 2014 Apr 16;4:CD009868) Fixed-dose therapy assumes that patients with multiple risks have no specific target organ damage at study recruitment and that each elevated levels of each risk factor had similar onset date. Such assumptions among other co-morbidities can translate into variable quality of life and prognosis.

Psychosocial comorbidities

NESARC was a survey of 43,093 participants that covered alcohol, drug and psychiatric disorders, risk factors, and consequences. NESARC Wave 1 (conducted in 2001-2002) had Wave 2 follow-up re-interviews (three years later) conducted among 34,653 of the original participants.

The most common disorders were alcohol, post traumatic stress disorders, and major depression. Females had more internalizing while males had more externalizing disorders and preponderance of alcohol disorders.

The “gender gap” was less pronounced than it was in previous decades. A race/ethnic “paradox” (lower risk among disadvantaged minorities than whites) remains unexplained. The young had higher risk for substance and personality disorders, but not unipolar depressive or anxiety disorders.

Psychiatric comorbidity was extensive and often formed latent trans-diagnostic domains. Since 1991-1992, risk for marijuana and prescription drug disorders increased. Smoking decreased, although less pronounced among those with comorbidity. A nexus of comorbidity, social support, and stress predicted transitions in diagnostic status between Waves 1 and 2.

Childhood maltreatment predicted psychopathology. The lack of treatment for alcohol and drug disorders, predicted by attitudinal rather than financial variables, suggests an urgent need for public and professional education to reduce the stigma associated with these disorders. (Hasin, Soc Psychiatry Psychiatr Epidemiol. 2015 Nov;50(11):1609-40.)

The other side of the coin

Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure (BP), are also found to relate to outcomes in the geriatric population, but in an opposite direction. Some degrees of elevated BMI, serum cholesterols, and BP are reportedly associated with lower, instead of higher, risk of death among the elderly, a phenomenon termed “reverse epidemiology” or “risk factor paradox” (such as obesity paradox) and is also observed in a variety of chronic disease states such as end-stage renal disease requiring dialysis, chronic heart failure, rheumatoid arthritis, and AIDS.

Several possible causes are hypothesized to explain this risk factor reversal, thereby affecting short-term and long-term prognoses, improved hemodynamic stability in the obese, adipokine protection against tumor necrosis factor-a, lipoprotein protection against endotoxins, and lipophilic toxin sequestration by the adipose tissue. It is possible that the current thresholds for intervention and goal levels for such traditional risk factors as BMI, serum cholesterol, and BP derived based on younger populations do not apply to the elderly.

Thus, new levels for such risk factors should be developed for the elderly population, a minority if not excluded group in most clinical trials. Reverse epidemiology of conventional cardiovascular risk factors may have a bearing on the management of the geriatric population. (Ahmadi, J Am Med Dir Assoc. 2015 Sep 9. pii: S1525-8610(15)00493-4)

Vital Signs Issue 84 Vol. 4, February 1-29 2016