|
The antihypertensive effects of COZAAR were demonstrated principally in 4 placebo-controlled, 6-to 12-week trials of dosages from 10 to 150 mg per day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparisons of two doses (50-100 mg/ day) as once-daily or twice-daily regimens, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Three additional studies examined the antihypertensive effects of losartan and hydrochlorothiazide in combination. The 4 studies of losartan monotherapy included a total of 1075 patients randomized to several doses of losartan and 334 to placebo. The 10-and 25-mg doses produced some effect at peak (6 hours after dosing) but small and inconsistent trough (24 hour) responses. Doses of 50, 100 and 150 mg once daily gave statistically significant systolic/ diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5-10.5/ 3.5-7.5 mmHg, with the 150-mg dose giving no greater effect than 50-100 mg. Twice-daily dosing at 50-100 mg/ day gave consistently larger trough responses than once-daily dosing at the same total dose. Peak (6 hour) effects were uniformly, but moderately, larger than trough effects, with the trough-to-peak ratio for systolic and diastolic responses 50-95% and 60-90%, respectively. Addition of a low dose of hydrochlorothiazide (12.5 mg) to losartan 50 mg once daily resulted in placebo-adjusted blood pressure reductions of 15.5/ 9.2 mmHg. Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65, had generally similar responses. COZAAR was effective in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-renin population). Text Continues Below
The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials. Reduction in the Risk of Stroke: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a multinational, double-blind study comparing COZAAR and atenolol in 9193 hypertensive patients with ECG-documented left ventricular hypertrophy. Patients with myocardial infarction or stroke within six months prior to randomization were excluded. Patients were randomized to receive once daily COZAAR 50 mg or atenolol 50 mg. If goal blood pressure (< 140/ 90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of COZAAR or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments (e. g., increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium-channel blockers, alpha-blockers, or centrally acting agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure. Of the randomized patients, 4963 (54%) were female and 533 (6%) were Black. The mean age was 67 with 5704 (62%) age 65. At baseline, 1195 (13%) had diabetes, 1326 (14%) had isolated systolic hypertension, 1469 (16%) had coronary heart disease, and 728 (8%) had cerebrovascular disease. Baseline mean blood pressure was 174/ 98 mmHg in both treatment groups. The mean length of follow-up was 4.8 years. At the end of study or at the last visit before a primary endpoint, 77% of the group treated with COZAAR and 73% of the group treated with atenolol were still taking study medication. Of the patients still taking study medication, the mean doses of COZAAR and atenolol were both about 80 mg/ day, and 15% were taking atenolol or losartan as monotherapy, while 77% were also receiving hydrochlorothiazide (at a mean dose of 20 mg/ day in each group). Blood pressure reduction measured at trough was similar for both treatment groups but blood pressure was not measured at any other time of the day. At the end of study or at the last visit before a primary endpoint, the mean blood pressures were 144.1/ 81.3 mmHg for the group treated with COZAAR and 145.4/ 80.9 mmHg for the group treated with atenolol [the difference in systolic blood pressure (SBP) of 1.3 mmHg was significant (p< 0.001), while the difference of 0.4 mmHg in diastolic blood pressure (DBP) was not significant (p= 0.098)]. The primary endpoint was the first occurrence of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Patients with non-fatal events remained in the trial, so that there was also an examination of the first event of each type even if it was not the first event (e. g., a stroke following an initial myocardial infarction would be counted in the analysis of stroke). Treatment with COZAAR resulted in a 13% reduction (p= 0.021) in risk of the primary endpoint compared to the atenolol group (see Figure 1 and Table 1); this difference was primarily the result of an effect on fatal and nonfatal stroke. Treatment with COZAAR reduced the risk of stroke by 25% relative to atenolol (p= 0.001) (see Figure 2 and Table 1). 0 6 12 18 24 30 36 42 48 54 60 66
Study Month 0
2
4
6
8
10
12
14
16 % patients with primary endpoint Atenolol COZAAR Adjusted Risk Reduction: 13%, p= 0.021 Figure 1. Kaplan-Meier estimates of the primary endpoint of time to cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction in the groups treated with COZAAR and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy. 0 6 12 18 24 30 36 42 48 54 60 66
Study Month 0 2
4
6
8 % patients with fatal/ non-fatal stroke Atenolol COZAAR Adjusted Risk Reduction: 25%, p= 0. 001
Figure 2. Kaplan-Meier estimates of the time to fatal/ nonfatal stroke in the groups treated with COZAAR and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy. Table 1 shows the results for the primary composite endpoint and the individual endpoints. The primary endpoint was the first occurrence of stroke, myocardial infarction or cardiovascular death, analyzed using an intention-to-treat (ITT) approach. The table shows the number of events for each component in two different ways. The Components of Primary Endpoint (as a first event) counts only the events that define the primary endpoint, while the Secondary Endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.
Table 1 Incidence of Primary Endpoint Events Primary Composite Endpoint
COZAAR Atenolol Risk
Reduction*
95%
CI
p-Value N (%) Rate* N (%) Rate*
508 (11) 23.8 588 (13) 27.9 13% 2% to 23% 0.021
Components of Primary Composite Endpoint (as a first event)
Stroke (nonfatal*) 209 (5) 286 (6)
Myocardial infarction (nonfatal*) 174 (4) 168 (4)
Cardiovascular mortality 125 (3) 134 (3) Secondary Endpoints (any time in study)
Stroke (fatal/ nonfatal) 232 (5) 10.8 309 (7) 14.5 25% 11% to 37% 0.001
Myocardial infarction (fatal/ nonfatal) 198 (4) 9. 2 188 (4) 8. 7 -7% -13% to 12% 0.491
Cardiovascular mortality 204 (4) 9. 2 234 (5) 10.6 11% -7% to 27% 0.206
Due to CHD 125 (3) 5. 6 124 (3) 5. 6 -3% -32% to 20% 0.839
Due to Stroke 40 (1) 1. 8 62 (1) 2. 8 35% 4% to 67% 0.032
Other§ 39 (1) 1. 8 48 (1) 2. 2 16% -28% to 45% 0.411
* Rate per 1000 patient-years of follow-up
* Adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy
* First report of an event, in some cases the patient died subsequently to the event reported §Death due to heart failure, non-coronary vascular disease, pulmonary embolism, or a cardiovascular cause other than stroke or coronary heart disease Although the LIFE study favored COZAAR over atenolol with respect to the primary endpoint (p= 0.021), this result is from a single study and, therefore, is less compelling than the difference between COZAAR and placebo. Although not measured directly, the difference between COZAAR and placebo is compelling because there is evidence that atenolol is itself effective (vs. placebo) in reducing cardiovascular events, including stroke, in hypertensive patients. Other clinical endpoints of the LIFE study were: total mortality, hospitalization for heart failure or angina pectoris, coronary or peripheral revascularization procedures, and resuscitated cardiac arrest. There were no significant differences in the rates of these endpoints between the COZAAR and atenolol groups. For the primary endpoint and stroke, the effects of COZAAR in patient subgroups defined by age, gender, race and presence or absence of isolated systolic hypertension (ISH), diabetes, and history of cardiovascular disease (CVD) are shown in Figure 3 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
Figure 3 Primary Endpoint Events* within Demographic Subgroups Overall Results Age
<65 years 65 years Gender Female
Male
Race Black White Other #
ISH Yes
No
Diabetes Yes No
History of CVD Yes No 9193
3489 5704 4963 4230
533 8503
157 1326 7867 1195 7998
2307 6886 No. of Patients
11
7 13 9 14
17 11
9 11 11 18 10
19 8 COZAAR Event
Rate (%) 13
7 16 11 15
11 13
14 16 12 23 11
21 10 Atenolol Event
Rate (%) Primary Composite # Other includes Asian, Hispanic, Asiatic, Multi-race, Indian, Native American, European.
Symbols are proportional to sample size. * Adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy. 0.3 0. 5 1 2 3 Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Favors COZAAR Favors Atenolol
5
3 6 4 6
9 5
5 5 5 9 5
9 4 COZAAR Event
Rate (%) 7
3 9 6 7
5 7
5 8 6 11 6
11 6 Atenolol Event
Rate (%) Stroke (Fatal/ Non-fatal) 0.3 0. 5 1 2 3
Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Hazard Ratio (95% CI) Favors COZAAR Favors Atenolol Race In the LIFE study, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with COZAAR. In the subgroup of Black patients (n= 533; 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-years) on COZAAR. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study provides no evidence that the benefits of COZAAR on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients. Nephropathy in Type 2 Diabetic Patients: The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a randomized, placebo-controlled, double-blind, multicenter study conducted worldwide in 1513 patients with type 2 diabetes with nephropathy (defined as serum creatinine 1.3 to 3.0 mg/ dl in females or males 60 kg and 1.5 to 3.0 mg/ dl in males >60 kg and proteinuria [urinary albumin to creatinine ratio 300 mg/ g]). Patients were randomized to receive COZAAR 50 mg once daily or placebo on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists. After one month, investigators were instructed to titrate study drug to 100 mg once daily if the trough blood pressure goal (140/ 90 mmHg) was not achieved. Overall, 72% of patients received the 100-mg daily dose more than 50% of the time they were on study drug. Because the study was designed to achieve equal blood pressure control in both groups, other antihypertensive agents (diuretics, calcium-channel blockers, alpha- or beta-blockers, and centrally acting agents) could be added as needed in both groups. Patients were followed for a mean duration of 3.4 years. The study population was diverse with regard to race (Asian 16.7%, Black 15.2%, Hispanic 18.3%, White 48.6%). Overall, 63.2% of the patients were men, and 66.4% were under the age of 65 years. Almost all of the patients (96.6%) had a history of hypertension, and the patients entered the trial with a mean serum creatinine of 1.9 mg/ dl and mean proteinuria (urinary albumin/ creatinine) of 1808 mg/ g at baseline. The primary endpoint of the study was the time to first occurrence of any one of the following events: doubling of serum creatinine, end-stage renal disease (ESRD) (need for dialysis or transplantation), or death. Treatment with COZAAR resulted in a 16% risk reduction in this endpoint (see Figure 4 and Table 2). Treatment with COZAAR also reduced the occurrence of sustained doubling of serum creatinine by 25% and ESRD by 29% as separate endpoints, but had no effect on overall mortality (see Table 2). The mean baseline blood pressures were 152/ 82 mmHg for COZAAR plus conventional antihypertensive therapy and 153/ 82 mmHg for placebo plus conventional antihypertensive therapy. At the end of the study, the mean blood pressures were 143/ 76 mmHg for the group treated with COZAAR and 146/ 77 mmHg for the group treated with placebo. 012 2436 48
Months 0 20
40
60 %
patients with
event p= 0.022
Risk Reduction = 16.1% COZAAR
Placebo Figure 4: Kaplan-Meier curve for the primary composite endpoint of doubling of serum creatinine, end stage renal disease (need for dialysis or transplantation) or death.
Table 2 Incidence of Primary Endpoint Events Primary Composite Endpoint
Incidence Risk Reduction 95% C. I. p-Value Losartan Placebo
43.5% 47.1% 16.1% 2.3% to 27.9% 0.022
Doubling of Serum Creatinine, ESRD and Death Occurring as a First Event
Doubling of Serum Creatinine 21.6% 26.0%
ESRD 8. 5% 8. 5%
Death 13.4% 12.6% Overall Incidence of Doubling of Serum Creatinine, ESRD and Death
Doubling of Serum Creatinine 21.6% 26.0% 25.3% 7.8% to 39.4% 0.006
ESRD 19.6% 25.5% 28.6% 11.5% to 42.4% 0.002
Death 21.0% 20.3% -1.7% -26.9% to 18.6% 0.884 The secondary endpoints of the study were change in proteinuria, change in the rate of progression of renal disease, and the composite of morbidity and mortality from cardiovascular causes (hospitalization for heart failure, myocardial infarction, revascularization, stroke, hospitalization for unstable angina, or cardiovascular death). Compared with placebo, COZAAR significantly reduced proteinuria by an average of 34%, an effect that was evident within 3 months of starting therapy, and significantly reduced the rate of decline in glomerular filtration rate during the study by 13%, as measured by the reciprocal of the serum creatinine concentration. There was no significant difference in the incidence of the composite endpoint of cardiovascular morbidity and mortality. The favorable effects of COZAAR were seen in patients also taking other anti-hypertensive medications (angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors were not allowed), oral hypoglycemic agents and lipid-lowering agents. For the primary endpoint and ESRD, the effects of COZAAR in patient subgroups defined by age, gender and race are shown in Table 3 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects. Table 3 Efficacy Outcomes within Demographic Subgroups
Primary Composite Endpoint ESRD
No. of
Patients
COZAAR
Event Rate
% Placebo
Event Rate
% Hazard Ratio
(95% CI)
COZAAR
Event Rate
% Placebo
Event Rate
% Hazard Ratio
(95% CI) Overall Results 1513 43.5 47.1 0. 839 (0.721, 0.977) 19.6 25.5 0. 714 (0.576, 0.885)
Age <65 years 1005 44.1 49.0 0. 784 (0.653, 0.941) 21.1 28.5 0. 670 (0.521, 0.863)
65 years 508 42.3 43.5 0. 978 (0.749, 1.277) 16.5 19.6 0. 847 (0.560, 1.281)
Gender
Female 557 47.8 54.1 0. 762 (0.603, 0.962) 22.8 32.8 0. 601 (0.436, 0.828)
Male 956 40.9 43.3 0. 892 (0.733, 1.085) 17.5 21.5 0. 809 (0.605, 1.081)
Race
Asian 252 41.9 54.8 0. 655 (0.453, 0.947) 18.8 27.4 0. 625 (0.367, 1.066)
Black 230 40.0 39.0 0. 983 (0.647, 1.495) 17.6 21.0 0. 831 (0.456, 1.516)
Hispanic 277 55.0 54.0 1. 003 (0.728, 1.380) 30.0 28.5 1. 024 (0.661, 1.586)
White 735 40.5 43.2 0. 809 (0.645, 1.013) 16.2 23.9 0. 596 (0.427, 0.831) Page: << Prev | 1 | 2 | 3 | 4 | 5
|
.gif)
