The study aims to assess the effective dose, safety and tolerability of telmisartan among Filipinos with mild to moderate essential hypertension. This will use the multicenter, open-labeled dose ranging study to outpatient clinic of 14 investigators in Metro Manila. A total of 200 men and women (mean age [Sd] , 53[10.8] years) with mean baseline supine systolic/diastolic blood pressure of 160 100 mmHg. Main outcome measure is to normalize supine diastolic blood pressure (<90mmHg) after4 weeks of treatment with telmisartan 40 mg or 80mg and adverse drug effects. Fourteen (14) 7% patients dropped out from the study for various reasons. Supine diastolic pressure was normalized in 143/200 (71.5%, with 95 percent CI OF 65% to 77.8%) of patients with majority of patients, 108/200 (54%), needing only the 40mg dose. Overall, 79% of patients had full response, 6.5% with partial response and 7.5% with minimal or no response to the 40-80mg dose tiltration of telmisartan. Three patients (1.5%) experienced treatment related adverse events. This multicenter open-labeled study showed that telmisartan is an effective and well-tolerated anti-hypertensive drug for Filipinos with mild to moderate hypertension. The dose needed by the majority of patients to normalize blood pressure was 40mg.
I. Introduction:
New therapeutic approach for inhibiting the activity of the rennin-angiotension system (RAS) is through Angiostension II receptor antagonism. Due to its good tolerability and absence of any class-specific adverse events, this new class of a drugs is rapidly establishing itself as a rational option in the treatment of hypertension.
Telmisartan, a new orally active, highly specific, nonpeptide substituted benzimidasole AT1 � receptor antagonist belongs to new class of drugs and has been shown to be an effective once a day treatment for hypertension with minimal side effects.
Clinical studies, however with telmisartan up to now have only been performed in Europe and North America. In order to determine the response of patients with a different racial background to telmisartan, this study was performed among Filipino patients with mild to moderate hypertensio
II. Body:
A. Study Population.
The study was conducted from the group of men and women 18 to 80 years of age. Patients have mild to moderate hypertension (mean supine diastolic blood pressure [DBP] 95-110mmHg and no significant metabolic or cardiovascular disease. Women of child bearing potential; individuals with significant renal, metabolic or cardiovascular disease, and anyone who had taken any investigational drug within 1 month of study start up were excluded.Informed consent was given to the included patients and protocol has approved by an institutional ethics committee and Bureau of Food and drugs (BFAD) and conducted in accordance with the Declaration of Helsinki.
B. Method
Two doses of telmisartan was been used, 40 mg and 80 mg for multi-center open label dose ranging study to assess the efficacy of drug and safety among Filipino hypertensive patients. The study included three periods: screening, placebo run-in and active treatment period:
B1. Screening.
Selected patients were assessed as to their demographic status together with history of present illness and physical examination, 12-lead electrocardiogram (ECG), and laboratory tests. Three measurement of blood pressure were taken 2 minutes apart with standard sphygmomanometer after the patient had rested supine for 5 minutes. Supine heart rate was measured during the two minutes between the first and second blood pressure readings. After third reading, the patient stood, and blood pressure was measured immediately. Two additional standing measurements were taken 2 minutes apart. The recorded reading was the mean of the three measurements.
B2. Placebo run-in
After inclusion/exclusion has been satisfied all subjects underwent a 4-week placebo run in wherein they were given placebo tablets once a day for 4 weeks. Subjects whose DBP was greater or equal 95 mmHg and less than 110mmHg at the end of this 4-week placebo run-in period were continued into the active treatment phase.
B3. Active treatment phase.
Patients were instructed to take 40 mg of telmisartan tablet once a day for four weeks. Preferred time for taking medication was 07.00 to 10.00 hours. If one dose was missed, patient was instructed to take next dose as scheduled. Medication should be taken on the day of visit, patient who failed had their visits rescheduled for the following day.
Preferred time for blood pressure measurement was 08.00, the acceptable window 07.00 to 10.00 hours. Patients were requested to arrive at the clinic not later than 24 hours (+4 hours) after the last dose of study drug.
Patient whose diastolic blood pressure had not been reduced to less than 90mmHg after 4 weeks of telmisartan 40 mg were given 80 mg of the drug for another 4 weeks.
Any antihypertensive drug or drug with known effect on blood pressure, narfarin, digoxin, digitoxin, chronic daily administration of more than two grams of aspirin or paracetamol, chronic high-dose use of non-steroidal anti-inflamatory agents if less than 3 months with stable dosage, chronic use of salt substitutes containing K+chloride, Lithium, neuroleptics, imipramine derivatives, short acting nitrites were not permitted.
Other treatments prescribed for concomitant disease (s) were allowed to be taken during the trial, and whenever possible at fixed dose. These were noted in the case report form.
C.Efficacy Evaluation.
The endpoint was to normalize the DBP (trough supine DBP <90mmHg) at the end of the 4-week 40 mg dose of telmisartan and at the end of 4 week 80 mg dose of the drug. Percentage of response in both dose of drug were also determined. The degree of DBP response was classified as follows: full: reduction from baseline in supine DBP at trough of greater or equal 10 mmHg and / or a trough supine DBP of less than 90 mmHg partial: reduction from baseline in supine DBP at trough of 5 to less than 10 mmHg with a trough supine DBP of greater or equal 90 mmHg; minimal or none: reduction from baseline in supine DBP at trough of less than 5 mmHg and trough supine DBP of greater or equal 90 mmHg, or any increase from baseline in supine DBP at trough, or discontinuations due to "lack of efficacy".
D.Safety Evaluation
Adverse events was monitored to ensure safety. All events were documented. Serious adverse events included those that were fatal or life-threatening, permanently or surely disabling, or that required prolonged hospitalization. Complete blood count and blood chemistries were evaluated as baseline and at the end of the 40 mg and / or 80 mg dosage period.
E. Statistical Analysis
Descriptive statistics were used to evaluate demographic variables and response to treatment. Based as estimated full response rate of 85% (as in previous studies) with the 40 mg dose and considering a width of confidence interval or 95% with a confidence level of 0.05, using the formula: N= (1-96)2 [p(1-p)] the calculated sample size was approximately 200 patients.
III. Results.
Only 11 subjects were newly diagnosed hypertensive patients. There were 38% with mild hypertension and 62% with moderate hypertension. There were 14 (7%) drop-outs and the reason for the drop out were the following lack of efficacy or worsening of hypertension (2), non-compliance with protocol (2), lost to follow-up (4), non-drug related adverse event (1), no reason given (5).
Once � daily termisartan 40 mg produced mean reductions from baseline in supine SBP and DBP of after 4 weeks of treatment were � 14.4 mmttg and �8.4 mmHg (SD,15.0, 7.8), respectively. For those placed on telmisartan 90 mg, the mean reductions in supine SBP and DBP from baseline up to end of treatment were �19.7 mmHg and �11.2 mmHg (SD, 11,4,6,2) respectively. Overall, trough supine diastolic blood pressure was normalized (<90 mmHg) in 143/200 (71.5% with 95% CI of 65.2% to 77.8%) of patients with 108/200 (54%) needing only 40 mg dose of telmisartan and an additional 35 patients (17%) needing an 80 mg dose. Classifying the overall, the response of the patients to the 40-80mg dose titration of telmisartan as full, partial or minimal or none, 158/200 (79%) had minimal or no response. Mean changes for the 40 mg telmisartan dose were �1.2 (SD,8.4) and �1.6 (SD, 8.7) respectively. On 80 mg dose, mean changes were �0.4 (SD, 8.1) and �1.6 (SD, 8.4).
There was a total of 32 treatment-emergent adverse events occurring in 23/200 patients (11.5%) most were mild and not considered as treatment-related. The three (1.5%) patients were assessed to have treatment � related adverse events. A patient experienced dizziness and headache while taking the 40-mg dose. Another patient reported hematoma on the left deltoid area while on 80mg dose; but disappear eventually. The third patient, while on 80 mg dose experienced palpitation which disappeared after 3 days. All these were judge to be mild and all three patients finished the treatment period. There was one incidence of slurring speech due to transient ischemic attack (TIA), but not treatment related.
IV. Discussion
Telmigartan, a new A 11 receptor antagonist given once a day, is an effective and well-tolerated antihypertensive drug when given once a day, is an effective and well-tolerated antihypertensive drug when given to Filipinos with mild to moderate hypertension. The 40 mg dose normalized the diastolic blood pressure of majority of the responders. The efficacy of the once daily dose of drug among the study population is consistent with studies done on Telmisartan has been shown to provide antihypertensive effect constantly over 24 hours and greater reduction in ambulatory blood pressure during the night time interval and during the last four hours of the dosing period compared with other long acting antihypertensive drugs, including losartan.
V.Conclusion
Telmisartan is an effective and well tolerated anti-hypertensive drug when given to Filipinos with mild to moderate hypertension. Majority of the responders needed only the 40 mg dose of the drug.
VI. References