Sequential drug decision problems in long-term medical conditions: a case Study of Primary Hypertension Eunju Kim ba, ma, msc
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- 5.6.3 5.6.4Conventional RR approach for the long-term CVD model
- 5.6.5 5.6.6Adverse effects
| Relative SLE (%) = (Absolute SLE / pre-treatment SBP)*100 Equation 5.7.
The average initial SBP of participants was 156.14 mmHg in Wald et al’s review and 168.88 mmHg in the Wright et al’s review; the relative SLE was fitted to the average of the initial SBPs from those two systematic reviews (i.e., 162.51 mmHg). Table 5. shows the relative SBP lowering effects where a single drug, two-drug combination or three-drug combination is used consistently over one year. As the SBP reduction due to the previous drugs were considered in the baseline SBP of each period, it was assumed that the SBP lowering effect of the first drug was not counted towards the effect of the second, third or fourth-line drug once a drug was switched. As the first-line drug was taken away and moved to the second, third and fourth-line drug, the SBP reduction due to the first drug should not remain over the next period because of the effect of stopping the first drug. Therefore, those values in the second column in Table 5. were used as the SBP lowering effect of the newly selected drug(s) and the incremental SBP lowering effects were used as the SBP lowering effect where the same drug was continuously used in the next cycle. Table 5.. Relative SBP lowering effects (%) accumulated over one year
1) SDs are given in parentheses. Appendix 6 provides the SDs of the individual studies included in the Wald et al’s and Wright et al’s systematic reviews. The pooled SDs are the weighted average of the individual SDs by the number of participants in each study. They were adjusted to a relative value based on the mean initial SBPs of the Wald et al’s and Wright et al’s systematic reviews (i.e., 162.51 mmHg) . 5.6.35.6.4Conventional RR approach for the long-term CVD modelThe conventional RR approach was used for the CVD prevention effect of antihypertensive drugs in the long-term CVD model. The RRs of antihypertensive drugs to UA, MI, Stroke and death were taken from the NICE hypertension models[63, 223]. The RRs to HF and DM were replaced with the up-to-date meta-analyses for the treatment effects of antihypertensive drugs on DM and HF[323, 324]. The same RRs were applied to patients with prior CVD identified (see Table 5.). The overall treatment effectiveness of combination treatment was calculated based on the multiplicative effect, as done in previous similar studies[276, 325, 326] (see Equation 5.8). For the joint effects of combination treatment, the RRs of each drug in the combination were assumed to be independent. , for two-drug combinations , for three-drug combinations Equation 5.8. Table 5.. Relative risks to CVDs, DM and death depending on antihypertensive drug
5.6.55.6.6Adverse effectsTwo systematic reviews that quantified the occurrence of AEs of antihypertensive drugs in primary hypertension were identified (see Table 5.). The primary interest of Ross’s systematic review was the prevalence of discontinuations due to AEs (DAEs)[278]. Compared with placebo, only CCBs had higher frequency of DAEs in treated patients, although the difference 0.0055 (95% CI -0.012 to 0.022) was not statistically significant. AE was also examined as the secondary outcome and categorised according to the World Health Organization Adverse Reaction Dictionary (WHOARD). Across drug classes, the occurrence of AEs was not significantly different to each other. Law et al’s systematic review examined the placebo-adjusted probability of the symptoms that might be plausibly caused by the antihypertensive drug[282]. The symptoms included dizziness, impotence, nausea, muscle cramp, skin rash, fatigue, cold extremities, dyspnoea, cough, back pain, flushing, ankle oedema and so on. At the standard dose, the percentages of persons with the undesirable symptoms attributable to Ds, BBs, CCBs, ACEIs and ARBs were 9.9%, 7.5%, 8.3%, 3.9% and 0% respectively. The placebo-adjusted prevalence of severe symptoms that stopped treatment with the drug were 0.1%, 0.8%, 1.4%, 0.1% and -0.2%, respectively. Compared with Ross et al’s review, Law et al’s review provided more comprehensive information including the AEs of combination treatment and adverse metabolic change. Law et al’s review showed that in 33 trial arms two drugs together caused the undesirable symptoms in 7.5% (95% CI 5.8-9.3%), which is significantly lower than the value of 10.4% (twice 5.2%) expected with an additive effect (p=0.03). Various metabolic changes such as abnormalities in glucose and lipid metabolism also have been examined: any adverse metabolic change in TC and its sub-fractions was negligible. This study selected the Law et al’s study by priority for the risk of AEs or DAEs for antihypertensive drugs. The reported incidence of AEs can be various depending on the definition and the thresholds for reporting AEs. It is also common that a patient has more than one AE. On the other hand, DAEs counts only one case per patient, whereas the actual timing of DAEs is rarely reported[278]. As DAEs are more explicit to capture the cases, the incidence of DAEs reported in Law et al’s study was used for the risk of AE in the base model, and the prevalence of AEs reported in the same study were tested in a sensitivity analysis. Table 5.. Comparison between Ross et al’s and Law et al’s systematic reviews
Based on the Law et al’s study, it was assumed that the AEs of two or three-drug combinations were less than an additive effect as following: Equation 5.9. It was assumed that this equation considers the interaction between the drugs combined implicitly. Depending on the combined drugs, the ratio may be various. Antihypertensive drugs from different classes may offset AEs from each other (e.g., Ds decrease edema occurring from CCBs[327]), or aggravate a specific AE (e.g., BBs, together with verapamil or diltiazem, may produce marked bradycardia and AV block, and may precipitate HF[328]; and ACEIs given together with a potassium-sparing D may cause the marked hyperkalemia[329]). However, these positive or negative interactions between the combined drugs were limited to be quantified. Yüklə 10,52 Mb. Dostları ilə paylaş:
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