Outcome Measures. Eligibility Criteria. Inclusion Criteria: Male or female, ambulatory outpatients years old at screening Have a history of hypertension Qualifying laboratory results Exclusion Criteria: Severe hypertension, including chronic kidney disease Documented congestive heart failure Have clinically significant respiratory, liver, or heart disease History of stroke, heart attack, or heart surgery in the last 6 months Have a history of hypersensitivity to nebivolol or other beta blockers.
Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.
More Information. Publications automatically indexed to this study by ClinicalTrials. Placebo effect and efficacy of nebivolol in patients with hypertension not controlled with lisinopril or losartan: a phase IV, randomized, placebo-controlled trial.
Am J Cardiovasc Drugs. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Drug: nebivolol Drug: Placebo. Phase 4. Study Type :. Interventional Clinical Trial. In a review of 61 studies comparing ARBs including losartan to ACE inhibitors including lisinopril , both categories of drugs were found to have similar long-term effects on blood pressure.
The authors also concluded that both classes of drugs have an equivalent effect on death, cardiovascular events, major adverse events, quality of life, and risk factors such as lipid levels, diabetes mellitus, and left ventricular mass and function.
In a small study of patients with kidney disease, losartan and lisinopril had similar effects on kidney function and blood pressure. The most effective medication for you should be determined by your doctor, who can look at the full picture of your medical condition s , history, and other medications you are taking.
Both losartan and lisinopril are covered by insurance and Medicare Part D in the generic form. The brand name versions may be covered at a higher copay.
You can save money on lisinopril by using a SingleCare discount card or coupon. Try the SingleCare prescription discount card. The most common side effects of losartan include cough, dizziness, upper respiratory infection, fatigue, and diarrhea.
The most common side effects of lisinopril include cough, dizziness, headache, fatigue, and diarrhea. Other side effects may occur.
Consult a healthcare professional for a complete list of side effects. Source: DailyMed losartan , DailyMed lisinopril. Losartan or lisinopril should not be used with potassium or other medications that increase potassium such as potassium-sparing diuretics , because of the risk of hyperkalemia.
Additionally, ask your doctor about potassium in your diet and if you should avoid potassium-rich foods and salt substitutes that contain potassium. NSAIDs nonsteroidal anti-inflammatory drugs should not be used in combination with losartan or lisinopril, because the combination could cause kidney injury or kidney failure.
Losartan or lisinopril should not be used in combination with another ACE inhibitor, ARB, or Tekturna aliskiren because the combination increases the risk of low blood pressure, high potassium, fainting, kidney damage, or kidney failure.
Losartan and lisinopril both come with a boxed warning, which is the strongest warning as required by the FDA. Losartan is an angiotensin receptor blocker that helps lower blood pressure. It can also be used for various other conditions, outlined above. Lisinopril is an ACE inhibitor that helps lower blood pressure.
It is also used for other medical conditions, outlined above. Similarly, two losartan dosing cohorts were assessed: 25mg daily to 50mg daily 50mg cohort and 50mg daily to mg daily mg cohort. Any regimens that did not align with these dosing cohorts were excluded e.
Patients could be included in two dosing cohorts if they experienced two eligible dose-doublings e. Patients also had to have at least one outpatient BP measurement in the six months before, or on the day of, the index date and at least one outpatient BP measurement two to 52 weeks after the index date to be included i. Because the sig contains unstructured free-text data [ 11 — 14 ], a text-processing tool was developed to extract the daily dosing frequency from the sig [ 15 ].
Briefly, the tool first standardizes all numbers, fractions, and characters e. Then, the tool standardizes all abbreviations and phrases e. Spelling errors are also corrected at this step e. The daily dosing frequency is derived from tallying the number of unique daily administrations.
The tool has a Sigs that were not assigned a dosing frequency by the tool were manually reviewed and assigned the correct dosing frequency. Patients with any dosing frequency except once-daily or twice-daily were excluded from the analysis.
The primary outcome was the follow-up SBP assessed at least two weeks and up to 52 weeks after the index date. If more than one measurement was taken on the same date, the average was used. Encounter of any type e. Encounters of any type with an ICD-9 code of Age, sex, race-ethnicity, education level, area-based US Census median family household income, tobacco use, comorbidities, body mass index BMI , SBP, DBP, serum creatinine, estimated glomerular filtration rate eGFR , serum potassium, albuminuria, number of BP measurements, and other BP-affecting medications that were dispensed and the patient had on-hand at the time of the index date were collected from the VDW in the 6 months prior to the index date.
Additional medications collected that affect BP included anti-anginals, beta-blockers, calcium channel blockers, diuretics, glucocorticosteroids, immunosuppressants, non-steroidal anti-inflammatory drugs, and selective norepinephrine reuptake inhibitors. Prescribing provider specialty was also included in the calculation of the propensity score, categorized as cardiology, family medicine, internal medicine, nephrology, nurse practitioner, pediatrics, urgent care, other, and missing.
Comorbidities were collected from ICD-9 and ICD codes attached to any type of encounter in the six months prior to the index date, which were used to calculate a baseline Charlson Comorbidity Index CCI score for each patient [ 17 ].
Analyses for all study outcomes occurred within dosing cohorts for each medication and were adjusted for covariates that were clinically and statistically associated with the receipt of twice-daily dosing using propensity scores i.
The propensity score was estimated using a multivariable logistic regression model to predict the probability of receiving twice-daily dosing based on gender, age, race, ethnicity, tobacco use, BMI, number of BP measurements before the index date, CCI, chronic pulmonary disease, congestive heart failure, depression, diabetes, chronic kidney disease, eGFR, albuminuria, other medications that affect BP, and provider specialty.
An analysis utilizing IPTW with stabilized weights was selected over other propensity score methods e. To evaluate the association between daily dosing frequency and BP, IPT-weighted linear regression models were constructed with the follow-up BP as the dependent variable, dosing frequency group as the independent variable, and baseline BP as a covariate.
To determine if the outcomes were sensitive to the implementation of IPTW, we also analyzed BP outcomes using unadjusted and multi-variable adjusted models. During the study period, 18, and 9, patients filled a prescription for a dose increase of lisinopril and losartan, respectively Fig 2. In the lisinopril 20mg cohort, the average number of BP measurements in the 6 months prior to the index date was 3. For the lisinopril 40mg cohort, the average number of BP measurements in the 6 months prior to the index date was 3.
Achieved systolic Panel A and diastolic blood pressure Panel B among patients taking twice-daily versus once-daily lisinopril and losartan. Sensitivity analyses evaluating unadjusted and multivariable adjusted models similarly found no differences in SBP between once-daily and twice-daily groups in either dosing cohort S4 Table.
However, there were unadjusted differences in DBP between the twice-daily and once-daily groups of In the losartan 50mg cohort, the average number of BP measurements in the 6 months prior to the index date was 4.
In the losartan mg cohort, the average number of BP measurements in the 6 months prior to the index date was 3. Similar to lisinopril, in both losartan dosing cohorts, there were no differences in follow-up SBP or DBP between the twice-daily and once-daily groups Table 1.
Patients taking twice-daily had lower odds of achieving SBP — mmHg compared to once-daily in both dosing cohorts 50mg OR 0. Additionally, patients who were taking losartan 25mg twice-daily had higher odds of achieving SBP — mmHg than those taking losartan 50mg once-daily OR 1.
Finally, patients who were taking losartan 50mg twice-daily had lower odds of achieving DBP 90—99 mmHg than those taking losartan mg once-daily OR 0. Significant differences in SBP and DBP observed in unadjusted models were rendered insignificant with multivariable adjustment S6 Table , except for SBP in patients taking losartan 25mg twice-daily compared to losartan 50mg once-daily absolute difference: There were no differences in the incidence of ADEs in the lisinopril twice-daily group compared to the lisinopril once-daily group Table 2 , except that patients taking lisinopril 10mg twice-daily had greater odds of experiencing angioedema and hyperkalemia than patients taking lisinopril 20mg once-daily angioedema OR 2.
There were no differences in the incidence of ADEs in the losartan twice-daily group compared to the losartan once-daily group Table 3. Patients taking twice-daily lisinopril or losartan were more likely to be older with higher comorbidity and medication burdens than those taking once-daily.
In IPTW-adjusted models, no statistically significant differences in SBP, DBP, or ADEs emerged between twice-daily and once-daily groups, except for an increased odds of experiencing angioedema and hyperkalemia with twice-daily dosing in the lower lisinopril dosing cohort. The findings of this study have significant implications for understanding the degree to which clinicians deviate from traditional dosing strategies to treat high BP in real-world practice.
The TPR relies on assessment of BP at only two time points and largely ignores the impacts of circadian rhythm or other activities that may be better assessed using ambulatory BP monitoring. In the clinical setting, other patient-specific factors such as medication adherence may also impact the decision to use nontraditional dosing frequencies.
As such, clinicians often employ a personalized approach to drug dosing by modifying the dosing frequency according to patient response, similar to published n -of-1 trials [ 30 , 31 ]; this strategy applied to altering dosing frequency has yet to be formally investigated as an effective means to improve BP control.
The current analysis provides evidence of the extent to which clinicians deviate from manufacturer-labeled recommendations for two commonly-used medications for high BP. Of 11, and 6, patients who met all inclusion and exclusion criteria for lisinopril and losartan, 7. Assuming that this prevalence mirrors general clinical practice and that 30 million Americans are prescribed lisinopril or losartan [ 32 ], it is possible that approximately 2.
More broadly, the prevalence of nontraditional dosing strategies for antihypertensive medications has not been investigated, and further, it is unknown whether nontraditional dosing strategies for hypertension treatment impact BP and clinical outcomes. Patients who are taking nontraditional antihypertensive medication regimens may serve as target populations for interventions to improve metrics and goals for BP control. Our findings support data generated from randomized trials and prospective cohort studies that have demonstrated no statistically significant differences in BP reduction or tolerability between once-daily and twice-daily dosing strategies of other ACEIs ramipril, enalapril, trandolapril and ARBs losartan, eprosartan, irbesartan, olmesartan, valsartan, candesartan [ 33 — 41 ].
However, these studies lack generalizability to current practice by including or evaluating patients based on DBP values [ 33 , 34 , 36 — 38 , 41 ], excluding key chronic disease populations like heart failure or chronic kidney disease [ 33 — 37 , 41 ], or comparing dosing against placebo [ 36 , 38 , 41 ].
It is possible that pharmacokinetic data demonstrate greater BP reduction with twice-daily dosing in adults studied in controlled environments. However, the effectiveness and safety findings described in the current real-world study combined with adherence data supporting once-daily regimens [ 42 — 45 ] suggest that less-complex regimens should be favored for hypertension treatment. Applying evidence-based interventions that aim to reduce pill burden or reduce medication regimen complexity e.
The current study findings oppose our previous work [ 9 ] for several reasons. Thousands of patients met the inclusion criteria for all four dosing cohorts, compared to 90 patients for one dosing cohort previously. The previous study excluded patients who had a change in medications that might impact BP between baseline and follow-up measurements; whereas, the current study included concomitant BP-affecting medications in the propensity score model.
Unlike our previous study, given the large sample size, we were not able to review each medical record to confirm dosing regimens or the dosing regimen used at the time of the follow-up BP measurement. Finally, the average baseline BP in the lisinopril groups of the current study were lower than the baseline BP measurements in our previous study, and we currently included patients regardless of baseline BP control. Therefore, it is possible that patients included in the current study may have had controlled BP and underwent a change in dosing for other reasons, biasing the effect toward the null.
The current study is also limited by the retrospective design in one health system. Due to the large sample size created using administrative queries, we were not able to review all records to confirm indication for lisinopril or losartan, purpose of dose increase, or adverse effects not detectable with administrative queries e.
Further, we did not analyze adherence outcomes, but literature well-describes decrements in adherence with multiple-daily dosing [ 42 — 45 ]. Clinical decision-making by providers is highly complex, and both patient- and provider-specific factors may have influenced the decision to use twice-daily dosing over once-daily dosing. We accounted for several measured covariates with a propensity score model, however, it is possible that such complex or unmeasured factors could have impacted our findings.
The high level of missingness for prescriber specialty, although it did not impact estimation of the propensity score, could impact findings because a clinician may manage medications differently depending on his or her training background.
The BP measurements used in this study are subject to constraints of real-world BP measurement practices over 10 years.
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